Novel piperazine derivatives

ABSTRACT

The present invention is a chemical compound of formula (I)  
                 
 
     or a pharmaceutically acceptable salts, solvates and esters thereof, wherein R 1  to R 4 , A 1 , A 2  m and n are as described in the specification.

BACKGROUND

[0001] It has been recognized that obesity is a disease processinfluenced by environmental factors in which the traditional weight lossmethods of dieting and exercise need to be supplemented by therapeuticproducts (S. Parker, “Obesity: Trends and Treatments”, Scrip Reports,PJB Publications Ltd, 1996).

[0002] Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m . Obesity is a BMI greater than30 kg/m There are problems with this definition in that it does not takeinto account the proportion of body mass that is muscle in relation tofat (adipose tissue). To account for this, obesity can also be definedon the basis of body fat content: greater than 25% in males and greaterthan 30% in females.

[0003] As the BMI increases there is an increased risk of death from avariety of causes that is independent of other risk factors. The mostcommon diseases associated with obesity are cardiovascular disease(particularly hypertension), diabetes (obesity aggravates thedevelopment of diabetes), gall bladder disease (particularly cancer) andreproductive diseases. Research has shown that even a modest reductionin body weight can correspond to a significant reduction in the risk ofdeveloping coronary heart disease.

[0004] Compounds marketed as anti-obesity agents include Orlistat(XENICAL®) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fatabsorption directly and tends to produce a high incidence of unpleasant(though relatively harmless) side-effects such as diarrhoea. Sibutramine(a mixed 5-HT/noradrenaline re-uptake inhibitor) can increase bloodpressure and heart rate in some patients. The serotoninreleaser/re-uptake inhibitors fenfluramine (Pondimin®) anddexfenfluramine (Redux™) have been reported to decrease food intake andbody weight over a prolonged period (greater than 6 months). However,both products were withdrawn after reports of preliminary evidence ofheart valve abnormalities associated with their use. There is thereforea need for the development of a safer anti-obesity agent.

[0005] The non-selective 5-HT_(2C) receptor agonists/partial agonistsm-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine(TFMPP) have been shown to reduce food intake in rats (G. A. Kennett andG. Curzon, Psychopharmacol., 1988, 96, 93-100; G. A. Kennett, C. T.Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429-435) and toaccelerate the appearance of the behavioural satiety sequence (S. J.Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377).Recent findings from studies with mCPP in normal human volunteers andobese subjects have also shown decreases in food intake. Thus, a singledose of mCPP decreased food intake in female volunteers (A. E. S. Walshet al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetiteand body weight of obese male and female subjects during subchronictreatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol.,1997, 133, 309-312). The anorectic action of mCPP is absent in 5-HT₂Creceptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374,542-546) and is antagonised by the 5-HT_(2C) receptor antagonistSB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36,609-620). It seems therefore that mCPP decreases food intake via anagonist action at the 5-HT_(2C) receptor.

[0006] Other compounds which have been proposed as 5-HT_(2C) receptoragonists for use in the treatment of obesity include the substituted1-aminoethyl indoles disclosed in EP-A-0655440. CA-2132887 andCA-2153937 disclose that tricyclic 1-aminoethylpyrrole derivatives andtricyclic 1-aminoethyl pyrazole derivatives bind to 5-HT_(2C) receptorsand may be used in the treatment of obesity. WO-A-98/30548 disclosesaminoalkylindazole compounds as 5-HT_(2C) agonists for the treatment ofCNS diseases and appetite regulation disorders. WO 0035922 discloses2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as 5HT_(2C)agonists. Aralkyloxycarbonyl-substituted piperazine derivatives havebeen repeatedly described as nitrogen-protected piperazine syntheticintermediates (e.g. Org. Lett., 2000, 2(8), 1049-1051.

SUMMARY

[0007] The present invention is a new piperazine derivative, processesand intermediates for its preparation, to pharmaceutical compositionscontaining the compound of the invention and to a method of treatmentusing the compound. The active compound of the present invention isuseful in treating obesity and other disorders.

[0008] The invention is a compound of formula I or a pharmaceuticallyacceptable salt, solvate or ester therof

[0009] wherein

[0010] R¹ and R² are independently selected from hydrogen, alkyl,cycloalkyl, aryl and aralkyl or R¹ and R² together with the carbon atomto which they are attached form an unsubstituted 3- to 8-memberedcarbocyclic ring or a 3- to 8-membered ring which is substituted withalkyl;

[0011] R³ and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, aryl and aralkyl;

[0012] A¹ is oxygen or sulfur, wherein in case A¹ is oxygen and A² isunsubstituted phenyl one of R¹, R², R³ and R⁴ is not hydrogen

[0013] A² is unsubstituted aryl, unsubstituted heteroaryl orunsubstituted cycloalkyl or aryl, heteroaryl or cycloalkyl eachsubstituted with at least one substituent independently selected fromthe group consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl,alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl,cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy,arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy,tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, or whereinsaid alkyl, said cycloalkyl, said aryl, said aralkyl, said alkoxy, saidaralkoxy, said aryloxy, said alkoxycarbonyl, said cycloalkoxycarbonyl,said aryloxycarbonyl, said aralkoxycarbonyl, said heteroaryloxycarbonyl,said cycloalkoxy, said alkylsulfonyloxy, said arylsulfonyloxy, saidheteroarylalkoxy, said alkenyloxy, said tetrahydrofuranylalkoxy, saidalkynyloxy and said cycloalkylalkoxy are substituted with betweenone andthree substituents independently selected from the group consisting ofalkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy substitutedwith between one and three halogen, thiophenyl, aryl, amino,alkylcarbonyl and aryloxy, or two substituents of aryl, heteroaryl orcycloalkyl form, together with the carbon atoms to which they areattached, an unsubstituted 5- to 7-membered carbocyclic ring or asubstituted 5- to 7-membered carbocyclic ring with at least onesubstituent independently selected from the group consisting of alkyl,alkoxy and halogen;

[0014] n is 1 or 2;

[0015] m is zero or 1;

[0016] wherein 2-methyl-1-piperazinecarboxylic acid(4-nitrophenyl)methyl ester and 1-piperazinecarboxylic acid(4-(trifluoromethyl)phenyl)methyl ester are excluded.

[0017] It is an object of this invention to provide selective, directlyacting 5HT₂ receptor ligands for use in therapy and particularly for useas anti-obesity agents. It is a further object of this invention toprovide directly acting ligands selective for 5-HT_(2C) receptors, foruse in therapy and particularly for use as anti-obesity agents. It is afurther object of this invention to provide selective, directly acting5-HT_(2C) receptor ligands, preferably 5-HT_(2C) receptor agonists, foruse in therapy and particularly for use as anti-obesity agents.

DETAILED DESCRIPTION

[0018] The term “alkyl”, alone or in combination, signifies astraight-chain or branched-chain alkyl group with 1 to 10, preferably 1to 8 carbon atoms, more preferably a straight or branched-chain alkylgroup with 1-4 carbon atoms. Examples of straight-chain and branchedC₁-C₈ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, theisomeric heptyls and the isomeric octyls, preferably methyl, ethyl,propyl and isopropyl. Particularly preferred are methyl and ethyl.

[0019] The term “cycloalkyl”, alone or in combination, signifies acycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkylring with 3 to 6 carbon atoms. Examples of C₃-C₈ cycloalkyl arecyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl,methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl,methylcyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl,preferably cyclo-propyl and particularly cyclopentyl.

[0020] The term “alkoxy”, alone or in combination, signifies a group ofthe formula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.

[0021] The term “cycloalkoxy”, alone or in combination, signifies agroup of the formula cycloalkyl-O— in which the term “cycloalkyl” hasthe previously given significance, such as cyclohexyloxy.

[0022] The term “carbonyl” refer to a group of the formula —C(O)—.

[0023] The term “aryl”, alone or in combination, signifies a phenyl ornaphthyl group, preferably a phenyl group which optionally carries oneor more, preferably one to three substituents each independentlyselected from halogen, trifluoromethyl, amino, alkyl, aryloxy,alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy,carboxy, alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl,alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro and alkoxy,wherein alkoxy is optionally substituted with 1 to 3 halogen atoms.Preferred is phenyl.

[0024] The term “aryloxy”, alone or in combination, signifies a group ofthe formula aryl-O— in which the term “aryl” has the previously givensignificance. Phenyloxy is an example of such an aryloxy group.

[0025] The term “heteroaryl”, alone or in combination, signifies anaromatic 5 to 10, preferably 5- or 6-membered ring comprising 1 to 3atoms independently selected from nitrogen, oxygen or sulfur such ase.g. furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl,oxazolyl, pyrrolyl and benzothiadiazolyl. Preferred examples arepyridyl, thienyl, pyrazinyl, furyl, isoxazole, (1,2,4)oxadiazole andthiazolyl. Particularly preferred are pyridyl and thienyl.

[0026] The term “heteroarylalkoxy”, alone or in combination, signifiesan alkoxy group as defined before, wherein one or two, preferably onehydrogen atom is replaced by a heteroaryl group as defined before.Examples are pyridin-3-ylmethoxy, isoxazol-4-ylmethoxy,(1,2,4)oxadiazol-3-ylmethoxy, 3-furylmethoxy, thien-3-ylmethoxy,isoxazol-3-ylmethoxy, thien-2-methoxy, (2,1,3)benzothiadiazolylmethoxy,2-thiophen-2-yl-ethoxy, 2-pyrrol-1-yl-ethoxy and thiazol-4-ylmethoxy.

[0027] The term “aralkyl”, alone or in combination, signifies an alkylor cycloalkyl group as previously defined in which one or several,preferably one hydrogen atom has been replaced by an aryl group aspreviously defined. Preferred is benzyl.

[0028] The term “3- to 8-membered carbocyclic ring” as used for thedefinition of R¹ and R² signifies a 3- to 8-membered, preferably 3 to 6membered cycloalkane ring. Examples are cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane and cyclooctane, preferablycyclopropane.

[0029] The term “5- to 7-membered carbocyclic ring” as used for thedefinition of A² signifies a cycloalkane ring with 5 to 7, preferably 6carbon atoms optionally substituted with alkyl, alkoxy or halogen.Examples are cyclopentane, methyl-cyclopentane, cyclohexane,methylcyclohexane, dimethyl-cyclohexane and cycloheptane preferablycyclohexane.

[0030] The term “aralkoxy”, alone or in combination, signifies an alkoxyor cycloalkoxy group as previously defined in which one or several,preferably one hydrogen atom has been replaced by an aryl group aspreviously defined. Preferred is benzyloxy.

[0031] The term “nitro”, alone or in combination, signifies a —NO₂group.

[0032] The term “cyano”, alone or in combination, signifies a —CN group.

[0033] The term “alkoxycarbonyl”, alone or in combination, signifies analkoxy-C(O)— group, wherein alkoxy is defined as before.

[0034] The term “cycloalkoxycarbonyl”, alone or in combination,signifies an cycloalkoxy-C(O)— group, wherein cycloalkoxy is defined asbefore.

[0035] The term “aryloxycarbonyl”, alone or in combination, signifies anaryloxy-C(O)— group, wherein aryloxy is defined as before.

[0036] The term “aralkoxycarbonyl”, alone or in combination, signifiesan aralkoxy-C(O)— group, wherein aralkoxy is defined as before.

[0037] The term “heteroaryloxycarbonyl”, alone or in combination,signifies a heteroaryl-O—C(O)— group, wherein heteroaryl is defined asbefore.

[0038] The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substitutents togetherforming a ring, such as, for example, —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl orpiperidino etc., preferably amino, dimethylamino and diethylamino andparticularly primary amino.

[0039] The term “halogen” signifies fluorine, chlorine, bromine oriodine and preferably fluorine, chlorine or bromine and particularlyfluorine and chlorine.

[0040] The term “carbamoyl” alone or in combination refers to a group ofthe formula NH(R′)—C(O)—, wherein R′ means hydrogen, alkyl, cycloalkyl,aryl, aralkyl, heteroaryl, adamantyl, alkenyl or alkyl substituted withhalogen. Preferably R′ means alkyl or aralkyl particularly preferred areisopropyl, benzyl and tert. butyl.

[0041] The term “carbamoyloxy”, alone or in combination, signifies acarbamoyl-O— group, wherein carbamoyl is defined as before.

[0042] The term “alkylsulfonyloxy”, alone or in combination, signifies a

[0043] group in which alkyl is as previously defined. An examples ispropylsulfonyloxy.

[0044] The term “arylsulfonyloxy”, alone or in combination, signifies a

[0045] group in which aryl is as previously defined. An examples isphenylsulfonyloxy.

[0046] The term “alkenyl”, alone or in combination, signifies astraight-chain or branched-chain hydrocarbon group comprising ancarbon-carbon double bond and 1 to 10, preferably 1 to 8 carbon atoms,more preferably 1-4 carbon atoms.

[0047] The term “alkenyloxy”, alone or in combination, signifies analkenyl-O— group, wherein alkenyl is defined as before.

[0048] The term “alkynyl”, alone or in combination, signifies astraight-chain or branched-chain hydrocarbon group comprising ancarbon-carbon triple bond and 1 to 10, preferably 1 to 8 carbon atoms,more preferably 1-4 carbon atoms.

[0049] The term “alkynyloxy”, alone or in combination, signifies analkynyl-O— group, wherein alkynyl is defined as before.

[0050] The term “oxo”, alone or in combination, signifies an ═O group.

[0051] Examples of pharmaceutically acceptable salts of the compounds offormula I are salts with physiologically compatible mineral acids suchhydrochloric acid, sulfuric acid or phosphoric acid; or with organicacids such as methanesulphonic acid, acetic acid, trifluoroacetic acid,citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid orsalicylic acid. Preferred salts of compounds of formula I arehydrochloride salts, succinate salts and fumarate salts. The compoundsof formula I can also form salts with physiologically compatible bases.Examples of such salts are alkali metal, alkali earth metal, ammoniumand alkylammonium salts such as the Na, K, Ca or tetramethylammoniumsalt. The compound of formula I can also be present in the form ofzwitterions.

[0052] The invention expressly includes pharmaceutically acceptablederivatives of the compounds of formula I. For example hydroxy groups ofcompounds of formula I can be esterified. Examples of such esters areformate, acetate, propionate, butyrate, isobutyrate, valerate,2-methylbutyrate, isovalerate and N,N-dimethylaminoacetate. Preferredesters are acetate and N,N-dimethylaminoacetate.

[0053] Also included are pharmaceutically acceptable solvates ofcompounds according to formula I such as for example hydrates. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration).

[0054] The term “lipase inhibitor” refers to compounds that are capableof inhibiting the action of lipases, for example gastric and pancreaticlipases. For example, orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitors of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterised in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to orlistat.

[0055] Orlistat is a known compound useful for the control or preventionof obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul.1, 1986, which also discloses processes for making orlistat and U.S.Pat. No. 6,004,996, which discloses appropriate pharmaceuticalcompositions. Further suitable pharmaceutical compositions are describedfor example in International Patent Applications WO 00/09122 and WO00/09123. Additional processes for the preparation of orlistat aredisclosed in European Patent Applications Publication Nos. 185,359,189,577, 443,449, and 524,495.

[0056] Orlistat is preferably orally administered from 60 to 720 mg perday in divided doses two to three times per day. Preferred is whereinfrom 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitoris administered to a subject, preferably in divided doses two or,particularly, three times per day. The subject is preferably an obese oroverweight human, i.e. a human with a body mass index of 25 or greater.Generally, it is preferred that the lipase inhibitor be administeredwithin about one or two hours of ingestion of a meal containing fat.Generally, for administering a lipase inhibitor as defined above it ispreferred that treatment be administered to a human who has a strongfamily history of obesity and has obtained a body mass index of 25 orgreater.

[0057] Orlistat can be administered to humans in conventional oralcompositions, such as, tablets, coated tablets, hard and soft gelatincapsules, emulsions or suspensions. Examples of carriers which can beused for tablets, coated tablets, dragées and hard gelatin capsules arelactose, other sugars and sugar alcohols like sorbitol, mannitol,maltodextrin, or other fillers; surfactants like sodium lauryl sulfate,Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maizestarch or derivatives thereof; polymers like povidone, crospovidone;talc; stearic acid or its salts and the like. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Moreover, the pharmaceuticalpreparations can contain preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. They can also contain stillother therapeutically valuable substances. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods known in the pharmaceutical art. Preferably, orlistat isadministered according to the formulation shown in the Examples and inU.S. Pat. No. 6,004,996, respectively.

[0058] The compounds of formula I can contain several asymmetric centersand can be present in the form of optically pure enantiomers, mixturesof enantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbents or eluent).

[0059] The term “asymmetric carbon atom (C*) means a carbon atom withfour different substituents. According to theCahn-Ingold-Prelog-Convention the asymmetric carbon atom can be of the“R” or “S” configuration.

[0060] Preferred are compounds according to formula I, wherein

[0061] R¹ and R² are independently selected from hydrogen, alkyl,cycloalkyl, aryl and aralkyl or R¹ and R² together with the carbon atomto which they are attached form a 3- to 8-membered carbocyclic ringwhich is optionally substituted with alkyl;

[0062] R³ and R⁴ are independently selected from hydrogen, alkyl,cycloalkyl, aryl and aralkyl;

[0063] A¹ is oxygen or sulfur, wherein in case A¹ is oxygen and A² isunsubstituted phenyl, one of R¹, R², R³ and R⁴ is not hydrogen;

[0064] A² is aryl, heteroaryl or cycloalkyl each optionally substitutedwith one or more substituents independently selected from halogen,alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy,cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and carbamoyl,wherein alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy,alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyland heteroaryloxycarbonyl are optionally substituted with one to threesubstituents independently selected from alkyl, alkoxy, halogen andnitro, or two substituents of aryl, heteroaryl or cycloalkyl formtogether with the carbon atoms to which they are attached a 5- to7-membered carbocyclic ring which is optionally substituted with alkyl,alkoxy or halogen;

[0065] n is 1 or 2 and

[0066] m is zero.

[0067] More preferred compounds according to formula I are those whereinR³ and R⁴ are independently selected from hydrogen and alkyl,mostpreferably R³ and R⁴ are hydrogen.

[0068] In another preferred embodiment, R³ and R⁴ are both alkyl.Additional preferred compounds are those wherein R³ and R⁴ are methyl.Most preferred are the compounds according to formula I, wherein R³ andR⁴ are methyl and both methyl groups have the cis configuration.Preferred are the cis-2,6-dimethylpiperazine derivatives of the formulaI, wherein R³ and R⁴ are methyl and R¹, R², A¹, A², m and n are definedas mentioned before.

[0069] A further preferred embodiment of the invention are compoundsaccording to formula I, wherein one of R³ and R⁴ is methyl or ethyl andthe other one is hydrogen.

[0070] Particularly preferred are chiral compounds of formula (Ia),

[0071] wherein R⁵ is alkyl, particularly methyl or ethyl, and R¹, R²,A¹, A², m and n are defined as before. Formula Ia means that theasymmetric carbon atom C*

[0072] is of the R configuration.

[0073] Further preferred compounds of formula I are those, wherein A¹ issulfur. Most preferred compounds of formula I are those wherein A¹ isoxygen.

[0074] Also preferred compounds of formula I are those wherein R¹ and R²are independently selected from hydrogen, alkyl, cycloalkyl, aryl andaralkyl or R¹ and R² together with the carbon atom to which they areattached form a 3- to 8-membered cycloalkyl ring which is optionallysubstituted with alkyl. A particularly preferred embodiment of theinvention comprises compounds of formula I, wherein R¹ and R² areindependently selected from hydrogen, alkyl and aryl, preferablyhydrogen, methyl and phenyl. Most preferred are those compounds, whereinR¹ and R² are both hydrogen.

[0075] Preferred are compounds according to formula (I), wherein A² isaryl, heteroaryl or cycloalkyl each optionally substituted with one ormore, preferably one to four, particularly preferred one to threesubstituents independently selected from halogen, alkyl, cycloalkyl,aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino,alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy,arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy,tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, wherein alkyl,cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl,cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,heteroaryloxycarbonyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy,heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy andcycloalkylalkoxy are optionally substituted with one to threesubstituents independently selected from alkyl, alkoxy, halogen, nitro,oxo, trifluoromethyl, alkoxy substituted with one to three halogen,thiophenyl, aryl, amino, alkylcarbonyl and aryloxy, or two substituentsof aryl, heteroaryl or cycloalkyl form together with the carbon atoms towhich they are attached a 5- to 7-membered carbocyclic ring which isoptionally substituted with one or more, preferably one to threesubstituents independently selected from alkyl, alkoxy and halogen.

[0076] Likewise preferred are compounds of the present invention,wherein A² is phenyl, naphthalenyl, cycloalkyl, pyridyl, thienyl,pyrazinyl or furyl, each optionally substituted with one or more,preferably one to four substituents, independently selected fromhalogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy,hydroxy, cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and carbamoyl,wherein alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy,alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyland heteroaryloxycarbonyl are optionally substituted with one to threesubstituents independently selected from alkyl, alkoxy, halogen andnitro, or two substituents of aryl, heteroaryl or cycloalkyl formtogether with the carbon atoms to which they are attached a 5- to7-membered carbocyclic ring which is optionally substituted with alkyl,alkoxy or halogen.

[0077] Preferred are compounds according to formula I, wherein A² isphenyl, naphthalenyl, cyclohexyl, pyridyl or thienyl each optionallysubstituted with one or more, preferably one to four substituentsindependently selected from halogen, alkyl, cycloalkyl, aryl, aralkyl,alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl,cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,heteroaryloxycarbonyl and carbamoyl, wherein alkyl, cycloalkyl, aryl,aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl, cycloalkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl and heteroaryloxycarbonyl areoptionally substituted with one to three substituents independentlyselected from alkyl, alkoxy, halogen and nitro. Particularly preferredexamples of the above substituents of phenyl, naphthalenyl, cyclohexyl,pyridyl and thienyl are trifluoromethoxyl, fluoro, chloro, bromo, nitro,phenylmethoxy, trifluoromethyl, methyl, tert-butyl, difluoromethoxy,cyano, methoxycarbonyl, benzyloxy, fluoro-benzyloxy, chlorobenzyloxy andnitrobenzyloxy.

[0078] Particularly preferred are compounds of formula I are those,wherein A² is phenyl, naphthalenyl, cyclohexyl, pyridyl or thienyl eachoptionally substituted with one or more, preferably one to foursubstituents independently selected from halogen, alkyl, aryl, alkoxy,aralkoxy, cyano, nitro, alkoxycarbonyl, wherein alkyl, alkoxy, aralkoxyand alkoxycarbonyl are optionally substituted with one to threesubstituents independently selected from halogen and nitro.

[0079] Other preferred compounds of formula I are those wherein A isphenyl, optionally substituted with one to five, preferably one to threesubstituents independently selected from halogen, alkyl, aryl, alkoxy,aralkoxy, cyano, nitro, alkoxycarbonyl, wherein alkyl, alkoxy andaralkoxy optionally substituted with one to three substituentsindependently selected from halogen and nitro.

[0080] A further preferred object of the present invention are compoundsaccording to formula I, wherein n is 1.

[0081] Another preferred object of the present invention are compoundsaccording to formula I, wherein A² is phenyl, optionally substitutedwith one to four substituents independently selected from halogen,alkoxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy, alkynyloxy andcycloalkylalkoxy, wherein alkoxy, heteroarylalkoxy and alkenyloxy areoptionally substituted with one to three substituents independentlyselected from alkyl and halogen. Particularly, preferred are compoundsof formula I, wherein A² is phenyl, optionally substituted with one tothree substituents independently selected from fluoro, chloro,difluoromethoxy, propoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy,2-propenyloxy, 5-pentyloxy, cyclopropylmethoxy, 2-propynyloxy andNH(R′)—C(O)—O—, wherein R′ is isopropyl, benzyl or tert.-butyl.

[0082] Additionally preferred compounds of formula I are those wherein mis zero.

[0083] Examples of preferred compounds of formula I include:

[0084] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl ester;

[0085] piperazine-1-carboxylic acid 3,4-difluoro-benzyl ester;

[0086] piperazine-1-carboxylic acid 4-fluoro-benzyl ester;

[0087] piperazine-1-carboxylic acid 4-bromo-benzyl ester;

[0088] piperazine-1-carboxylic acid 2-trifluoromethoxy-benzyl ester;

[0089] piperazine-1-carboxylic acid 2-chloro-5-nitro-benzyl ester;

[0090] piperazine-1-carboxylic acid 2-chloro-benzyl ester;

[0091] piperazine-1-carboxylic acid biphenyl-4-ylmethyl ester;

[0092] piperazine-1-carboxylic acid 3-methoxy-benzyl ester;

[0093] piperazine-1-carboxylic acid 3-trifluoromethyl-benzyl ester;

[0094] piperazine-1-carboxylic acid 4-trifluoromethyl-benzyl ester;

[0095] piperazine-1-carboxylic acid naphthalen-2-ylmethyl ester;

[0096] piperazine-1-carboxylic acid naphthalen-1-ylmethyl ester;

[0097] piperazine-1-carboxylic acid 2-methyl-benzyl ester;

[0098] piperazine-1-carboxylic acid 2,4-dichloro-benzyl ester;

[0099] piperazine-1-carboxylic acid 2,6-dichloro-benzyl ester;

[0100] piperazine-1-carboxylic acid 4-tert-butyl-benzyl ester;

[0101] piperazine-1-carboxylic acid 2-fluoro-4-trifluoromethyl-benzylester;

[0102] piperazine-1-carboxylic acid 2,4-difluoro-benzyl ester;

[0103] piperazine-1-carboxylic acid 2-chloro-4-fluoro-benzyl ester;

[0104] piperazine-1-carboxylic acid 4-fluoro-2-trifluoromethyl-benzylester;

[0105] piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl ester;

[0106] piperazine-1-carboxylic acid 2,4-dimethyl-benzyl ester;

[0107] piperazine-1-carboxylic acid cyclohexylmethyl ester;

[0108] piperazine-1-carboxylic acid 2-fluoro-benzyl ester;

[0109] cis-2,6-dimethyl-piperazine-1-carboxylic acid 4-chloro-benzylester;

[0110] cis-2,6-dimethyl-piperazine-1-carboxylic acid 3-cyano-benzylester;

[0111] cis-2,6-dimethyl-piperazine-1-carboxylic acid4-methoxycarbonyl-benzyl ester;

[0112] piperazine-1-carboxylic acid 4-cyano-benzyl ester;

[0113] piperazine-1-carboxylic acid 2-trifluoromethyl-benzyl ester;

[0114] piperazine-1-carboxylic acid 4-chloro-2-fluoro-benzyl ester;

[0115] piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)ester;

[0116] piperazine-1-carbothioic acid S-(4-bromo-benzyl)ester;

[0117] piperazine-1-carbothioic acid S-(4-trifluoromethoxy-benzyl)ester;

[0118] piperazine-1-carbothioic acid S-(4-fluoro-benzyl)ester;

[0119] piperazine-1-carbothioic acid S-(2,4-difluoro-benzyl)ester;

[0120] piperazine-1-carbothioic acid S-(4-methoxy-benzyl)ester;

[0121] piperazine-1-carbothioic acid S-(2,4-dimethyl-benzyl)ester;

[0122] piperazine-1-carbothioic acid S-(2-fluoro-4-trifluoromethyl-benzyl)ester;

[0123] piperazine-1-carbothioic acidS-[4-(4-fluoro-benzyloxy)-benzyl]ester;

[0124] piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester;

[0125] piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl ester;

[0126] piperazine-1-carboxylic acid 4-methoxy-benzyl ester;

[0127] piperazine-1-carboxylic acid benzhydryl ester;

[0128] (RS)-piperazine-1-carboxylic acid 1-phenyl-ethyl ester;

[0129] piperazine-1-carboxylic acid phenethyl ester;

[0130] cis-2,6-dimethylpiperazine-1-carboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester;

[0131] piperazine-1-carboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester;

[0132] cis-2,6-dimethylpiperazine-1-carboxylic acid 2-(2-thienyl)ethylester;

[0133] cis-2,6-dimethylpiperazine-1-carboxylic acid 2-fluoro-benzylester;

[0134] piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzylester;

[0135] piperazine-1-carboxylic acid 3-(2-phenethyloxy)-benzyl ester

[0136] 3-[2-(3-chlorophenyl)]ethoxybenzyl piperazine-1-carboxylate;

[0137] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester;

[0138] 4-bromo-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0139] benzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0140] 2-chlorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0141] (R)-2-fluorobenzyl 2-methylpiperazine-1-carboxylate;

[0142] 2-fluoro-4-propylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0143] S-4-[(ethylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate;

[0144] S-4-[[(2-chloroethyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0145] S-4-[(butylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate;

[0146] S-4-[(2-propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0147] S-4-[(benzylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0148] S-4-[[(2-methylbenzyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0149] 4-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0150] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester;

[0151] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester;

[0152] 4-ethyl-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0153] 2-fluoro-4-pentylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0154] S-4-[(tert-butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0155] 2,5-difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0156] 2,3-difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0157] 2,6-difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0158] 2,4-dimethylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0159] 2-4-[(propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0160] S-4-[(cyclohexylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0161] 2-fluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0162] 3-benzyloxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0163] 2,6-difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0164] (+/−)-S-4-[(2-butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0165] S-4-[(cyclopentylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0166] S-4-[(1-adamantylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0167] S-4-[(2-propenylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0168] S-4-[(phenylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0169] S-4-[[4-(2-propylphenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0170] (+/−)-S-4-[[(1-phenylethyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0171]S-4-[[[(4-ethoxycarbonyl)phenyl]amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0172] S-4-[[(3-chloro-4-fluorophenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0173]S-4-[[(4-difluoromethoxyphenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0174] 4-methylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0175] (+/−)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;

[0176] S-4-[[(4-methoxyphenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0177] S-4-[[(3-methylbenzyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0178] S-4-[[(4-methoxybenzyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0179] 2,6-difluoro-4-(2-propyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0180] S-4-(2-oxo-2-phenylethoxy)benzyl piperazine-1-thiocarboxylate;

[0181] (R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;

[0182] S-4-benzenesulfonyloxybenzyl piperazine-1-thiocarboxylate;

[0183] (+/−)-2,6-difluoro-4-propoxybenzyl2-ethylpiperazine-1-carboxylate;

[0184] (+/−)-2,6-difluoro-4-difluoromethoxybenzyl2-ethylpiperazine-1-carboxylate;

[0185] 2-fluoro-5-methoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0186] 3-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0187] S-4-propanesulfonyloxybenzyl piperazine-1-thiocarboxylate;

[0188] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(pyridin-3-ylmethoxy)-benzyl ester;

[0189] (R)-2,6-difluoro-4-propoxybenzyl2-methylpiperazine-1-carboxylate;

[0190] (R)-4-difluoromethoxybenzyl 2-methylpiperazine-1-carboxylate;

[0191] 5-benzyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0192] 2,6-difluoro-4-(3-phenyl)propoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0193] 4-bromo-2-fluorobenzyl piperazine-1-carboxylate;

[0194] 2,6-difluoro-4-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0195] (R)-2,6-difluoro-4-difluoromethoxybenzyl2-methylpiperazine-1-carboxylate;

[0196] 2-fluoro-5-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0197] 5-ethoxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0198] 2-fluoro-5-propoxybenzyl piperazine-1-carboxylate;

[0199] (R)-2-fluoro-5-propoxybenzyl 2-methylpiperazine-1-carboxylate;

[0200] 2-fluoro-5-propoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0201] 5-butoxy-2-fluorobenzyl piperazine-1-carboxylate;

[0202] (R)-5-butoxy-2-fluorobenzyl 2-methylpiperazine-1-carboxylate;

[0203] 5-butoxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0204] cis-2,6-dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;

[0205] 2-fluoro-5-(2-methylpropyl)-oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0206] 2-chloro-6-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0207] (R)-2,6-difluorobenzyl 2-methylpiperazine-1-carboxylate;

[0208] (R,R)-4-difluoromethoxybenzyl2,6-dimethylpiperazine-1-carboxylate;

[0209] (R)-2-fluoro-5-(2-propenyl)oxybenzyl2-methylpiperazine-1-carboxylate;

[0210] 2-fluoro-5-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0211] 5-(cyclohexylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0212] 2-fluoro-5-(2-phenyl)ethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0213] 2-fluoro-1-(3-phenyl)propoxybenzyl piperazine-1-carboxylate;

[0214] (R)-2-fluoro-5-(3-phenyl)propoxybenzyl2-methylpiperazine-1-carboxylate;

[0215] 2-fluoro-5-(3-phenyl)propoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0216] 2-fluoro-5-(3trifluoromethylbenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0217] 2-fluoro-5-(2-pyridylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0218] 2-fluoro-5-(3-pyridylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0219] (+/−)-2,6-difluoro-4-(2-pyridylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate;

[0220] (+/−)-2,6-difluoro-4-(3-pyridylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate;

[0221] (+/−)-2-methyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;

[0222] 5-tert-butylaminocarbonyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0223] 2-fluoro-5-(4-difluoromethoxybenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0224] piperazine-1-carboxylic acid2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzylester;

[0225] (R)-2-methyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzylester;

[0226] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzylester;

[0227] 2,6-difluoro-4-(3-fluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0228] 2,6-difluoro-4-(3,4-difluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0229] 2-fluoro-5-(2,4-difluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0230] 2-fluoro-5-(3,4-difluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0231] 2,6-difluoro-4-(3-furylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0232] (+/−)-2,6-difluoro-4-(3-furylmethyl)oxybenzyl2-ethylpiperazine-1-carboxylate;

[0233] (+/−)-piperazine-1-carboxylic acid2,6-difluoro-4-(tetrahydro-furan-2-ylmethoxy)-benzyl ester;

[0234] (+/−)-piperazine-1-carboxylic acid2-fluoro-4-(tetrahydro-furan-2-ylmethoxy)-benzyl ester;

[0235] 2,6-difluoro-4-(3-thienylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0236] 2,6-difluoro-4-(3-thienylmethyl)oxybenzylpiperazine-1-carboxylate;

[0237] (R)-2,6-difluoro-4-(3-thienylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate;

[0238] (+/−)-2,6-difluoro-4-(3-thienylmethyl)oxybenzyl2-ethylpiperazine-1-carboxylate;

[0239] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-methyl-isoxazol-3-ylmethoxy)-benzyl ester;

[0240] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-benzyl ester;

[0241] (+/−)-2-fluoro-5-(2-propenyl)oxybenzyl2-ethylpiperazine-1-carboxylate;

[0242] 2-fluoro-5-(2-propenyl)oxybenzyl piperazine-1-carboxylate;

[0243] 2,6-difluoro-4-(2-thienylmethyl)oxybenzylpiperazine-1-carboxylate;

[0244] (R)-2,6-difluoro-4-(2-thienylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate;

[0245] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(thiophen-2-ylmethoxy)-benzyl ester;

[0246] 5-butylaminocarbonyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0247] 2-fluoro-5-(2-propynyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0248] 5-(5-[2,1,3]benzothiadiazolylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0249] 2-fluoro-5-(3-fluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0250] (R)-2-fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate;

[0251] 5-(cyclopropylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0252] (R)-2-methyl-piperazine-1-carboxylic acid2-fluoro-5-(2-thiophen-2-yl-ethoxy)-benzyl ester;

[0253] cis-2,6-dimethyl-piperazine-1-carboxylic acid3-bromo-2,6-difluoro-benzyl ester;

[0254] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,4-difluoro-2′-methoxy-biphenyl-3-ylmethyl ester;

[0255] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,4-difluoro-3′,4′-dimethoxy-biphenyl-3-ylmethyl ester;

[0256] cis-2,6-dimethyl-piperazine-1-carboxylic acid2,4-difluoro-3′-hydroxy-4′-methoxy-biphenyl-3-ylmethyl ester;

[0257] cis-2,6-dimethyl-piperazine-1-carboxylic acid3′-amino-2,4-difluoro-biphenyl-3-ylmethyl ester;

[0258] cis-2,6-dimethyl-piperazine-1-carboxylic acid4′-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester;

[0259] cis-2,6-dimethyl-piperazine-1-carboxylic acid3′-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester;

[0260] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-methyl-benzyl ester;

[0261] (R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-benzylester;

[0262] (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester;

[0263] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-propoxy-benzyl ester;

[0264] (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester;

[0265] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester;

[0266] (R)-2-ethyl-piperazine-1-carboxylic acid4-butoxy-2,6-difluoro-benzyl ester;

[0267] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl ester;

[0268] (R)-2-ethyl-piperazine-1-carboxylic acid4-ethoxy-2,6-difluoro-benzyl ester;

[0269] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl ester;

[0270] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-methoxy-benzyl ester;

[0271] (R)-2-ethyl-piperazine-1-carboxylic acid 5-ethoxy-2-fluoro-benzylester;

[0272] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-propoxy-benzyl ester;

[0273] (R)-2-ethyl-piperazine-1-carboxylic acid 5-butoxy-2-fluoro-benzylester;

[0274] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-pentyloxy-benzyl ester;

[0275] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-(3-methyl-butoxy)-benzyl ester;

[0276] (R)-2-ethyl-piperazine-1-carboxylic acid5-benzyloxy-2-fluoro-benzyl ester;

[0277] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-phenethyloxy-benzyl ester;

[0278] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-(2-methyl-benzyloxy)-benzyl ester;

[0279] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-(3-methyl-benzyloxy)-benzyl ester;

[0280] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-(2-pyrrol-1-yl-ethoxy)-benzyl ester;

[0281] (R)-2-ethyl-piperazine-1-carboxylic acid5-cyclopropylmethoxy-2-fluoro-benzyl ester;

[0282] (R)-2-ethyl-piperazine-1-carboxylic acid5-cyclobutylmethoxy-2-fluoro-benzyl ester;

[0283] (R)-2-ethyl-piperazine-1-carboxylic acid5-cyclohexylmethoxy-2-fluoro-benzyl ester;

[0284] (R)-2-ethyl-piperazine-1-carboxylic acid5-(2-cyclohexyl-ethoxy)-2-fluoro-benzyl ester;

[0285] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-prop-2-ynyloxy-benzyl ester;

[0286] (R)-2-ethyl-piperazine-1-carboxylic acid5-allyloxy-2-fluoro-benzyl ester;

[0287] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-(2-methoxy-ethoxy)-benzyl ester;

[0288] (R)-2-ethyl-piperazine-1-carboxylic acid5-(2-ethoxy-ethoxy)-2-fluoro-benzyl ester;

[0289] (R)-2-ethyl-piperazine-1-carboxylic acid2-fluoro-5-(3-phenoxy-propoxy)-benzyl ester;

[0290] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-methoxy-benzyl ester;

[0291] (R)-2-ethyl-piperazine-1-carboxylic acid3-ethoxy-2,6-difluoro-benzyl ester;

[0292] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-propoxy-benzyl ester;

[0293] (R)-2-ethyl-piperazine-1-carboxylic acid3-butoxy-2,6-difluoro-benzyl ester;

[0294] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-pentyloxy-benzyl ester;

[0295] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-methyl-butoxy)-benzyl ester;

[0296] (R)-2-ethyl-piperazine-1-carboxylic acid3-benzyloxy-2,6-difluoro-benzyl ester;

[0297] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-phenyl-propoxy)-benzyl ester;

[0298] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(4-methyl-benzyloxy)-benzyl ester;

[0299] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-methyl-benzyloxy)-benzyl ester;

[0300] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(2-methyl-benzyloxy)-benzyl ester;

[0301] (R)-2-ethyl-piperazine-1-carboxylic acid3-(3,3-dimethyl-butoxy)-2,6-difluoro-benzyl ester;

[0302] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(2-pyrrol-1-yl-ethoxy)-benzyl ester;

[0303] (R)-2-ethyl-piperazine-1-carboxylic acid3-cyclopropylmethoxy-2,6-difluoro-benzyl ester;

[0304] (R)-2-ethyl-piperazine-1-carboxylic acid3-cyclobutylmethoxy-2,6-difluoro-benzyl ester;

[0305] (R)-2-ethyl-piperazine-1-carboxylic acid3-(2-cyclohexyl-ethoxy)-2,6-difluoro-benzyl ester;

[0306] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-prop-2-ynyloxy-benzyl ester;

[0307] (R)-2-ethyl-piperazine-1-carboxylic acid3-allyloxy-2,6-difluoro-benzyl ester;

[0308] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(2-methoxy-ethoxy)-benzyl ester;

[0309] (R)-2-ethyl-piperazine-1-carboxylic acid3-(2-ethoxy-ethoxy)-2,6-difluoro-benzyl ester;

[0310] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-phenoxy-propoxy)-benzyl ester;

[0311] (R)-2-ethyl-piperazine--carboxylic1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]ester;

[0312] (R)-2-ethyl-piperazine-1-carboxylic acid1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]ester;

[0313] (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester;

[0314] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-propoxy-benzyl ester;

[0315] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-ethoxy-benzyl ester;

[0316] (R)-2-ethyl-piperazine-1-carboxylic acid4-butoxy-2-chloro-6-fluoro-benzyl ester;

[0317] (R)-2-ethyl-piperazine-1-carboxylic acid4-butoxy-2-chloro-6-fluoro-benzyl ester;

[0318] (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester;

[0319] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester;

[0320] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzyl ester;

[0321] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzyl ester;

[0322] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl ester.

[0323] Examples of particularly preferred compounds of formula I are:

[0324] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl ester;

[0325] piperazine-1-carboxylic acid 2-chloro-benzyl ester;

[0326] piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl ester;

[0327] piperazine-1-carboxylic acid 2-fluoro-benzyl ester;

[0328] cis-2,6-dimethyl-piperazine-1-carboxylic acid 4-chloro-benzylester;

[0329] piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)ester;

[0330] piperazine-1-carbothioic acid S-(2,4-difluoro-benzyl)ester;

[0331] piperazine-1-carbothioic acid S-(4-methoxy-benzyl)ester;

[0332] piperazine-1-carbothioic acidS-[4-(4-fluoro-benzyloxy)-benzyl]ester;

[0333] piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl ester;

[0334] cis-2,6-dimethylpiperazine-1-carboxylic acid 2-(2-thienyl)ethylester;

[0335] cis-2,6-dimethylpiperazine-1-carboxylic acid 2-fluoro-benzylester;

[0336] 4-bromo-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0337] 2-fluoro-4-propylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0338] S-4-[(butylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylate;

[0339] S-4-[(2-propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0340] S-4-[(benzylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0341] 4-difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0342] 4-ethyl-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0343] S-4-[(tert-butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0344] 2,6-difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0345] 2-fluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0346] 3-benzyl oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate;

[0347] 2,6-difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0348] (+/−)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;

[0349] S-4-(2-oxo-2-phenylethoxy)benzyl piperazine-1-thiocarboxylate;

[0350] (R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;

[0351] (R)-2,6-difluoro-4-propoxybenzyl2-methylpiperazine-1-carboxylate;

[0352] (R)-4-difluoromethoxybenzyl 2-methylpiperazine-1-carboxylate;

[0353] 2-fluoro-5-propoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0354] cis-2,6-dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;

[0355] (R)-2-fluoro-5-(2-propenyl)oxybenzyl2-methylpiperazine-1-carboxylate;

[0356] 2-fluoro-5-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0357] (R)-2-fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate;

[0358] 5-(cyclopropylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0359] (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester;

[0360] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-propoxy-benzyl ester;

[0361] (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester;

[0362] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester;

[0363] (R)-2-ethyl-piperazine-1-carboxylic acid5-allyloxy-2-fluoro-benzyl ester;

[0364] (R)-2-ethyl-piperazine-1-carboxylic acid3-allyloxy-2,6-difluoro-benzyl ester;

[0365] (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester;

[0366] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-propoxy-benzyl ester;

[0367] (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester;

[0368] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester.

[0369] Most preferred compounds according to formula I are:

[0370] S-4-[(2-propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0371] S-4-[(benzylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0372] S-4-[(tert-butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate;

[0373] 2,6-difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0374] (R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;

[0375] (R)-2,6-difluoro-4-propoxybenzyl2-methylpiperazine-1-carboxylate;

[0376] cis-2,6-dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;

[0377] 2-fluoro-5-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0378] (R)-2-fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate;

[0379] 5-(cyclopropylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;

[0380] (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester;

[0381] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-propoxy-benzyl ester;

[0382] (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester;

[0383] (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester;

[0384] (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester;

[0385] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-propoxy-benzyl ester;

[0386] (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester and

[0387] (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester.

[0388] Processes for the manufacture of the compounds according toformula I are an object of the present invention. The substituents andindices used in the following schemes have the significance given aboveunless indicated to the contrary.

[0389] Compounds of formula (I) where R¹ to R⁴, A¹, A² and n are aspreviously defined may be conveniently prepared according to ReactionScheme 1.

[0390] A compound of formula (VI) can be prepared by reaction of thepiperazine carbamoyl chloride (III) with an alcohol (IV) or thiol (V) inthe presence of a suitable base such as sodium hydride, triethylamine,PS-BEMP or pyridine in a solvent such as acetonitrile,N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran ordichloromethane. The piperazine may be protected using a suitableprotecting group (P) e.g. tert-butoxycarbonyl,9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl,3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and9-fluorenylmethoxycarbonyl. These protective groups may also be bound toa polymeric resin, e.g., polystyrene-PEG-bound trityl.

[0391] The protected piperazine-carbamoyl chloride (III) may besynthesized from a protected piperazine (II) by treatment with a reagentsuch as phosgene, diphosgene or triphosgene in the presence of a basesuch as pyridine in a suitable solvent, for instance dichloromethane.Where necessary, protected piperazines (II) can be synthesized fromcommercially available monoalkyl- or dialkyl-piperazines by treatmentwith reagents known to introduce the desired protecting group e.g.di-tert-butyl dicarbonate or 9-fluorenylmethyl chloroformate. Theprotection of the piperazines may also be accomplished by covalentlinkage of the appropriate piperazine nitrogen to a polymeric resin,e.g., polystyrene-PEG-hydroxytrityl resin in the case of P=trityl, usingmethods known in the art. Mono or dialkyl-piperazines may be prepared bythose skilled in the art via a variety of methods which includes, but isnot limited to: reduction of mono or dialkylpyrazines using e.g.catalytic hydrogenation or dissolved metal reagents; alkylation ofethylene diamine and alkylated analogues with e.g. alkyl-substituted1,2-dihaloethane compounds, alkyl-substituted 1,2-ethanediol compoundsor alkyl-substituted ethane-1,2-dialkylsulfonate compounds; reduction ofa monoalkyl substituted 2,5-diketopiperazine with e.g. sodium or lithiumborohydride or lithium aluminium hydride.

[0392] The alcohol (IV) may be commercially available or alternativelymay be synthesized via reduction of an aldehyde, carboxylic acid, esteror amide derivative with a reagent such as sodium or lithium borohydrideor lithium aluminium hydride in a suitable solvent or alternatively viaGrignard addition of alkyl- or aryl-magnesium halides or alkyl- oraryl-lithium nucleophiles to aldehydes or carboxylic esters or amides.The aldehydes, carboxylic acids, esters and amides may be commerciallyavailable or synthesized according to methods known to those skilled inthe art. Such methods include but are not limited to formylation of anaryl or heteroaryl containing starting-material, vicarious nucleophilicsubstitution, hydrolysis of an alkyl halide or oxidation of anaryl-methyl (tolyl) group.

[0393] Thiols of formula (V) may be prepared from (IV) by a variety ofmethods e.g. displacement of an activated derivative of the hydroxyl of(IV) with a sulfur nucleophile such as thiolacetic acid followed bytreatment with a reducing agent such as lithium aluminium hydride.Activated hydroxyl derivatives include, but are not limited to,mesylates, tosylates and in situ activation with phosphorus compoundssuch as triphenylphosphine.

[0394] Thiols of formula (V) may be replaced by xanthogenates, which areprepared in situ from alcohol (IV) with carbon disulfide and a base suchas sodium or potassium hydroxide in a solvent such as tetrahydrofuran oracetone.

[0395] Compounds of formula (I) may be prepared from compounds offormula (VI) by reaction with a reagent known to selectively remove theprotecting group (P) e.g. tert-butoxycarbonyl, triphenylmethyl and3,4-dimethoxybenzyl may be removed using an acid such as hydrochloricacid or trifluoroacetic acid and 9-fluorenylmethoxycarbonyl may beremoved by treatment with a base such as morpholine.

[0396] Alternatively compounds of formula (I) where A¹═O may be preparedvia Reaction Scheme (2) below.

[0397] Reaction of a piperazine (II) with carbon dioxide in the presenceof a base such as tetraalkylammonium (for alkyl preferably ethyl orbutyl) hydrogencarbonate or potassium hydride or butyl-lithium or ametal such as lithium may produce the piperazine-carboxylate (VII).Treatment of (VII) with halide (VIII) (X means Cl, Br or I) in asuitable solvent may give a compound of formula (VI) where A¹═O. Halidesof formula (VIII) may be synthesized if not commercially available bymethods known to those skilled in the art. Such methods include, but arenot limited to, conversion of an alcohol of formula (IV) where A¹═O viatreatment with triphenylphosphine and a halogen such as bromine;formation and displacement of an alkyl or arylsulfonate such as mesylateor tosylate with a halide salt such as sodium bromide in a solvent suchas tetrahydrofuran or acetone and halogenation of an aralkyl orheteroaralkyl compound with a reagent such as N-bromosuccinimideoptionally in the presence of a co-reagent such as AIBN(2,2′-azobisisobutyronitrile) or benzoyl peroxide. Compounds of formula(VI) can be transformed into compounds of formula (I) by methods asdescribed above in Reaction Scheme 1.

[0398] If, in any of the other processes mentioned herein, R¹, R², R³,R⁴ and the substituent groups attached to A² are other than the onerequired, the substituent group may be converted to the desiredsubstituent by known methods. R¹, R², R³, R⁴ and the substituent groupsattached to A² may also need protecting against the conditions underwhich the reaction is carried out. In such a case, the protecting groupmay be removed after the reaction has been completed.

[0399] Alternatively compounds of formula (I) where A¹═O may be preparedvia Reaction Scheme (3) below.

[0400] A compound of formula (VI) can be prepared by reaction of thepiperazine (II) with an activated derivative (IX) or (X) of alcohol (IV)optionally in the presence of a suitable base such as triethylamine,PS-BEMP or pyridine in a solvent such as acetonitrile,N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran ordichloromethane. The piperazine may be protected using a suitableprotecting group (P) e.g. tert-butoxycarbonyl,9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl,3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and9-fluorenylmethoxycarbonyl.

[0401] The activated derivative (IX) may be synthesizedsynthesized fromalcohol (IV) with 1-chloroalkyl chloroformate, preferably 1-chloroethylchloroformate, in the presence of a suitable base such as triethylamine,PS-BEMP or pyridine in a solvent such as acetonitrile,N-methylpyrrolidinone, dimethyl formamide, tetrahydrofuran ordichloromethane.

[0402] The activated derivative (X) is either commercially available ormay be synthesizedsynthesized from alcohol (IV) by treatment with areagent such as phosgene, diphosgene, or triphosgene, optionally in thepresence of a base such as pyridine, in a suitable solvent, e. g.,dichloromethane or tetrahydrofuran.

[0403] Compounds of formula (I) may be prepared from compounds offormula (VI) by reaction with a reagent known to selectively remove theprotecting group (P) e.g. tert-butoxycarbonyl and 3,4-dimethoxybenzylmay be removed using an acid such as hydrochloric acid ortrifluoroacetic acid and 9-fluorenylmethoxycarbonyl may be removed bytreatment with a base such as morpholine.

[0404] The processes as described above may be carried out to give acompound of the invention in the form of a free base or as an acidaddition salt. If the compound of the invention is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid addition salt. Conversely, if the product of the process is afree base, an acid addition salt, particularly a pharmaceuticallyacceptable acid addition salt, may be obtained by dissolving the freebase in a suitable organic solvent and treating the solution with anacid, in accordance with conventional procedures for preparing acidaddition salts from basic compounds.

[0405] A further object of the present invention is the process for thepreparation of a compound according to formula I comprising thedeprotection of a compound according to formula

[0406] wherein R¹ to R⁴, A¹, A², m and n are defined as before and (P)is a nitrogen protecting group. Examples of nitrogen protecting groupsare tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl,trimethylsilyl, 3,4-dimethoxybenzyl and trityl, preferablytert-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.

[0407] Another preferred aspect of this invention are the followingintermediates:

[0408] Cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester;

[0409] Piperazine-1,4-dicarboxylic acid tert-butyl ester4-trifluoromethoxy-benzyl ester;

[0410] Piperazine-1,4-dicarboxylic acid tert-butyl ester 2-fluoro-benzylester;

[0411] 4-(4-Benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylicacid tert-butyl ester;

[0412]4-[4-(4-Fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylicacid tert-butyl ester;

[0413] Piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester9H-fluoren-9-ylmethyl ester;

[0414] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester4-(4-fluoro-benzyloxy)-benzyl ester;

[0415] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester4-methoxy-benzyl ester;

[0416] Piperazine-1,4-dicarboxylic acid benzhydryl ester9H-fluoren-9-ylmethyl ester;

[0417] (RS)-Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester1-phenyl-ethyl ester;

[0418] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid5-(2-chloropyridyl)methyl ester tert-butyl ester;

[0419] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester;

[0420] Piperazine-1,4-dicarboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester;

[0421][(4-tert-Butyl-dimethylsilyloxy)benzylsulfanylcarbonyl]-piperazine-4-carboxylicacid tert-butyl ester;

[0422] Piperazine-1,4-dicarboxylic acid(3-tert-butyldimethylsilyloxy)benzyl ester tert-butyl ester;

[0423] Piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl estertert-butyl ester;

[0424] Piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl estertert-butyl ester;

[0425] 4-(4-Fluoro-benzyloxy)-phenyl-methanethiol;

[0426] (RS)-Carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester;

[0427] (RS)-Carbonic acid 1-chloro-ethyl ester4-(4-fluoro-benzyloxy)-benzyl ester;

[0428] (RS)-Carbonic acid 1-chloro-ethyl ester 4-methoxy-benzyl ester;

[0429] (RS)-Carbonic acid benzhydryl ester 1-chloro-ethyl ester;

[0430] (RS)-Carbonic acid 1-chloro-ethyl ester 1-phenyl-ethyl ester.

[0431] Use of the compounds of formula I as therapeutically activesubstances is a further object of the invention.

[0432] A further object of the invention are compounds of formula I asdescribed above for the production of medicaments for the prophylaxisand therapy of illnesses which are caused by disorders associated withthe 5-HT₂ receptor, particularly with the 5-HT_(2a), 5-HT_(2b) or5-HT_(2c) subtype. Most preferred is the 5-HT_(2c) subtype.

[0433] Likewise an object of the invention is a pharmaceuticalcomposition comprising a compound of formula I and a therapeuticallyinert carrier.

[0434] A further object of the invention is a compound of formula I forthe production of pharmaceutical compositions for the treatment andprophylaxis of eating disorders and obesity.

[0435] Also an object of the invention is the use of a compoundaccording to formula I for the production of medicaments for thetreatment of diabetes mellitus, Type I diabetes, Type II diabetes,diabetes secondary to pancreatic disease, diabetes related to steroiduse, Type III diabetes, hyperglycaemia, diabetic complications andinsulin resistance.

[0436] Particularly, a further object of the invention is the use of acompound of formula I for the production of medicaments for thetreatment of Type II diabetes.

[0437] Another object of the invention is the use of compounds inaccordance with formula I for the production of medicaments for thetreatment and prophylaxis of disorders of the central nervous system,cardiovascular disorders, gastrointestinal disorders, diabetes insipidusand sleep apnoea.

[0438] Particularly an object of the invention is the above method oftreatment, wherein the disorders of the central nervous system areselected from depression, atypical depression, bipolar disorders,anxiety disorders, obsessive-compulsive disorders, social phobias orpanic states, sleep disorders, sexual dysfunction, psychoses,schizophrenia, migraine and other conditions associated with cephalicpain or other pain, raised intracranial pressure, epilepsy, personalitydisorders, age-related behavioural disorders, behavioural disordersassociated with dementia, organic mental disorders, mental disorders inchildhood, aggressivity, age-related memory disorders, chronic fatiguesyndrome, drug and alcohol addiction, bulimia, anorexia nervosa,premenstrual tension, trauma, stroke, neurodegenerative diseases,encephalitis and meningitis.

[0439] A further preferred embodiment of the present invention is theabove mentioned method of treatment by administering the compoundsaccording to formula I, wherein the cardiovascular disorder isthrombosis.

[0440] Also preferred is the mentioned use of the compounds according toformula I, wherein the gastrointestinal disorder is dysfunction ofgastrointestinal motility.

[0441] A further object of the invention are compounds in accordancewith formula I, when manufactured according to the described process.

[0442] A further embodiment of the present invention is a method for thetreatment and prophylaxis of disorders of the central nervous system,cardiovascular disorders, gastrointestinal disorders, diabetesinsipidus, and sleep apnoea, which method comprises administering aneffective amount of a compound of formula I as described. Preferred isthis method, wherein the disorders of the central nervous system areselected from depression, atypical depression, bipolar disorders,anxiety disorders, obsessive-compulsive disorders, social phobias orpanic states, sleep disorders, sexual dysfunction, psychoses,schizophrenia, migraine and other conditions associated with cephalicpain or other pain, raised intracranial pressure, epilepsy, personalitydisorders, age-related behavioural disorders, behavioural disordersassociated with dementia, organic mental disorders, mental disorders inchildhood, aggressivity, age-related memory disorders, chronic fatiguesyndrome, drug and alcohol addiction, bulimia, anorexia nervosa,premenstrual tension, trauma, stroke, neurodegenerative diseases,encephalitis and meningitis.

[0443] A preferred object of the invention is a method for the treatmentand prophylaxis of eating disorders and obesity, which method comprisesadministering an effective amount of a compound of formula I.

[0444] Another object of the present invention is a method for thetreatment and prophylaxis of disorders selected from diabetes mellitus,Type I diabetes, Type II diabetes, diabetes secondary to pancreaticdisease, diabetes related to steroid use, Type III diabetes,hyperglycaemia, diabetic complications and insulin resistance, whichmethod comprises administering an effective amount of a compound inaccordance with formula I. Particularly preferred is the above methodfor the treatment and prophylaxis of Type II diabetes.

[0445] Particularly preferred is a method for the treatment andprophylaxis of Type II diabetes.

[0446] A further preferred object is a method of treatment of obesity ina human in need of such treatment which comprises administration to thehuman a therapeutically effective amount of a compound according toformula I and a therapeutically effective amount of a lipase inhibitor,particularly, wherein the lipase inhibitor is orlistat.

[0447] Also an object of the invention are the method as described abovefor the simultaneous, separate or sequential administration.

[0448] A further object of the invention is the use of a compound offormula I in the manufacture of a medicament for the treatment andprevention of obesity in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

[0449] Another object of the invention is the use of a compoundaccording to formula I in the manufacture of a medicament for thetreatment and prevention of diabetes mellitus, Type I diabetes, Type IIdiabetes, diabetes secondary to pancreatic disease, diabetes related tosteroid use, Type III diabetes, hyperglycaemia, diabetic complicationsand insulin resistance in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

[0450] Particularly preferred is the use of a compound according toformula I in the manufacture of a medicament for the treatment andprevention of Type II diabetes in a patient who is also receivingtreatment with a lipase inhibitor and particularly, wherein the lipaseinhibitor is orlistat.

[0451] Also an object of the invention is the pharmaceutical compositioncomprising a compound of formula I, a therapeutically inert carrier andfurther a therapeutically effective amount of a lipase inhibitor,particularly, wherein the lipase inhibitor is orlistat.

[0452] The compounds of formula (I) may be used in the treatment(including prophylactic treatment) of disorders associated with 5-HT₂receptor function. The compounds may act as receptor agonists orantagonists. Preferably, the compounds may be used in the treatment(including prophylactic treatment) of disorders associated with5-HT_(2b) and/or 5-HT_(2c) receptor function. Preferably, the compoundsmay be used in the treatment (including prophylactic treatment) ofdisorders where a 5-HT_(2c) receptor agonist is required.

[0453] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) transdermal or rectal administration orin a form suitable for administration by inhalation or insufflation.

[0454] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g. pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g. magnesium stearate,talc or silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulfate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters or ethyl alcohol); and preservatives (e.g.methyl or propyl p-hydroxybenzoates or sorbic acid).

[0455] For buccal administration the composition may take the form oftablets or lozenges formulated in conventional manner.

[0456] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents.

[0457] Alternatively, the active ingredient may be in powder form forreconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

[0458] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0459] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0460] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., obesity) is 0.1to 500 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

[0461] The invention will now be described in detail with reference tothe following examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

Assay Procedures

[0462] Binding to Serotonin Receptors

[0463] The binding of compounds of formula (I) to serotonin receptorswas determined in vitro by standard methods. The preparations wereinvestigated in accordance with the assays given below.

[0464] Method (a): For the binding to the 5-HT_(2C) receptor, the5-HT_(2C) receptors were radiolabeled with [³H]-5-HT. The affinity ofthe compounds for 5-HT_(2C) receptors in a CHO cell line was determinedaccording to the procedure of D. Hoyer, G. Engel and H. O. Kalkman,European J. Pharmacol., 1985, 118, 13-23.

[0465] Method (b): For the binding to the 5-HT_(2B) receptor, the5-HT_(2B) receptors were radiolabeled with [3H]-5-HT. The affinity ofthe compounds for human 5-HT_(2B) receptors in a CHO cell line wasdetermined according to the procedure of K. Schmuck, C. Ullmer, P.Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.

[0466] Method (c): For the binding to the 5-HT_(2A) receptor, the5-HT_(2A) receptors were radiolabeled with [¹²⁵I]-DOI. The affinity ofthe compounds for 5-HT_(2A) receptors in a CHO cell line was determinedaccording to the procedure of D. J. McKenna and S. J. Peroutka, J.Neurosci., 1989, 9, 3482-90.

[0467] The thus determined activity of the compound presented as acalculated Ki of the Example is shown in Table 1. The Ki value isdefinied as an inhibition Constance and is determined from the IC50value as described in Cheng, Yung-Chi and Prusoff, W. H., Biochem.Pharmacol., 1973, 22(23), 3099-108. TABLE 1 Method (a) Method (b) Method(c) Compound Ki (2C)/nM Ki (2B)/nM Ki (2A)/nM 32 15 370 6 22 44 4000 4463 33 8300 550 121 15 8400 200

[0468] Preferred Ki (2C) values are below 10000 nM; especially preferredKi (2C) values are below 1000 nM, particularly preferred Ki (2C) valuesare below 100 nM. Most preferred Ki (2C) values are below 50 nM.

[0469] Functional Activity

[0470] The functional activity of compounds of formula (I) was assayedusing a Fluorimetric Imaging Plate reader (FLIPR). CHO cells expressingthe human 5-HT_(2C) or human 5-HT_(2A) receptors were counted and platedinto standard 96 well microtitre plates on the day before testing togive a confluent monolayer. The cells were then dye loaded with thecalcium sensitive dye, Fluo-3-AM. Unincorporated dye was removed usingan automated cell washer to leave a total volume of 100 μL/well of assaybuffer (Hanks balanced salt solution containing 20 mM Hepes and 2.5 mMprobenecid). The drug (dissolved in 50 □L of the assay buffer) was addedat a rate of 70 μL/sec to each well of the FLIPR 96 well plate duringfluorescence measurements. The measurements were taken at 1 secintervals and the maximum fluorescent signal was measured (approx 10-15secs after drug addition) and compared with the response produced by 10μM 5-HT (defined as 100%) to which it was expressed as a percentageresponse (relative efficacy). Dose response curves were constructedusing Graphpad Prism (Graph Software Inc.). TABLE 2 h5-HT_(2c)h5-HT_(2A) Relative Relative EC50 Efficacy EC50 Efficacy Compound (nM)(%) (nM) (%) 32 38 65 560 22 22 100 56 220 24 63 33 74 370 25 121 22 91550 11

[0471] The compounds of formula (I) have activity at the h5-HT_(2C)receptor in the range of 10,000 to 0.1 nM.

[0472] Preferred activities at the h5-HT_(2C) receptor are below 10000nM; especially preferred below 1000 nM, particularly preferredactivities are below 100 nM. Most preferred activity at the h5-HT_(2C)receptor are below 50 nM.

[0473] The compounds of formula (I) have maximum functional activity atthe h5-HT_(2C) receptor in the range of 0 to 100%.

[0474] Preferred maximal functional activity at the h5-HT_(2C) receptoras described above are above 30%; especially preferred above 50%,particularly preferred above 60%. Most preferred maximal functionalactivity at the h5-HT_(2C) receptor are above 70%.

[0475] Regulation of Feeding Behaviour

[0476] The in vivo activity of compounds of formula (1) was assayed forability to regulate feeding behaviour by assaying food consumption infood deprived animals as follows.

[0477] Test compounds are assessed following acute administration. Eachstudy utilises a between-subjects design (typically n=8) and comparesthe effects of doses of the test agent to those of vehicle and apositive control.

[0478] The anorectic drug d-fenfluramine normally serves as a positivecontrol. The route of drug administration, drug volume andinjection-test-interval are dependent upon the compounds used. Apalatable wet mash, made by adding powdered lab chow and water in aratioof 1:2 and mixing to a smooth consistency, is presented in 120 mL glassjars for 60 minutes each day. Intake is measured by weighing before andafter each session. Care is taken to collect all spillage. Animals areallowed to habituate to the wet mash meal for 10 days. After drugadministration, animals are allowed to consume the wet mash. Foodconsumption is assayed at pre-determined time points (typically, 1, 2and 4 hours after administration). Food intake data are subjected toone-way analysis of variance (ANOVA) with drug as a between-subjectsfactor. A significant main effect is followed up by the performance ofDunnett's test in order to assess which treatment mean(s) aresignificantly different from the control mean. All statistical analyseswere performed using Statistica Software, Version 5.0 (Statsofr Inc.)and Microsoft Excel 7.0 (Microsoft Corp.).

[0479] The thus determined activity of the Example indicated that thecompounds maintain significant hypophagia 3 hours after a dose of 30mg/kg per os.

EXAMPLES

[0480] Abbreviations

[0481] PS-BEMP:2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazo-phosphorineon polystyrene

[0482] PS-NH2: 4-(Aminomethyl)-polystyrene

[0483] TBME: tert-Butyl methyl ether

[0484] Starting Materials

[0485] 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl esterwas prepared following a modified procedure of document DE 25 50 111,Rhone-Poulenc. (+/−)4-chlorocarbonyl-2-ethylpiperazine-1-carboxylic acidtert-butyl ester was prepared using the method described in DE 2550111according to the following procedure:

[0486] To a stirred solution of 2-ethylpiperazine dihydrochloride (J.Org. Chem., 1987, 52(6), 1045, 5.0 g) and triethylamine (9.3 ml) in DCM(50 ml) at 0° C. was added di-tert-butyl-dicarbonate (6.5 g). Themixture was warmed to room temperature, stirred for 2 h, washedsuccessively with water, dilute sodium hydroxide solution, water andbrine then dried (sodium sulfate) and concentrated in vacuo to give theproduct as a clear oil (5.1 g); δ_(H) (400 MHz, CDCl₃) 3.78 (1H, m),3.71 (1H, d, J 12.5 Hz), 2.81 (1H, dt, J 11.5, 2.5 Hz), 2.69 (1H, t, J10.5 Hz), 2.48 (1H, td, J 11.5, 3 Hz), 2.29 (1H, m), 2.17 (1H, m), 1.39(9H, s), 1.31 (1H, dd, J 7.5, 6 Hz), 1.25 (1H, dd, J 7.5, 6 Hz) and 0.87(3H, t, J 7 Hz); GC (150° C. −10 min-320° C.) 93%, 5.13 min.

[0487] (+/−)4-Chlorocarbonyl-2-ethylpiperazine-1-carboxylic acidtert-butyl ester: a solution of (RS)4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) and pyridine (1.64 ml)in DCM (35 ml) was added dropwise to a stirred solution of triphosgene(2.1 g) in DCM (100 ml) at 0° C. under Ar. The mixture was warmed toroom temperature, stirred for 30 min then washed with water (100 ml) andbrine (100 ml). The organic solution was dried (sodium sulfate) andconcentrated in vacuo. The residue was dissolved in isohexane, filteredand concentrated in vacuo to give the product as a clear oil (3.73 g)which was used without further purification; δ_(H) (400 MHz, CDCl₃)4.39-3.80 (4H, m), 3.39-2.69 (3H, m), 1.66 (2H, m), 1.47 (9H, s), 0.96(2.7H, d, J 7 Hz) and 0.89 (0.3H, d, J 7 Hz); GC (150° C. −10 min −320°C.) 83%, 8.72 min.

[0488] (+/−)4-chlorocarbonyl-2-methylpiperazine-1-carboxylic acidtert-butyl ester and (R)4-chlorocarbonyl-2-methylpiperazine-1-carboxylicacid tert-butyl ester were prepared according to the above method fromcommercially available racemic 2-methylpiperazine and(R)2-methylpiperazine respectively.

[0489] Tetrabutylammonium hydrogencarbonate was prepared as described inSt. C. Cheng, Ch. A. Blaine, M. G. Hill, K. R. Mann, Inorg. Chem. 35,7704 (1996); C. Venturello, R. D'Aloisio, Synthesis 1985, 33.

[0490] N-Boc-piperazine is commercially available.

[0491] N-Fmoc-piperazine hydrobromide is commercially available.

[0492] 4-(4-Fluorobenzyloxy)-benzyl alcohol is commercially available.

[0493] 4-(4-Fluoro-benzyloxy)-phenyl-methanethiol was prepared inanalogy to S. Vetter, Synth. Commun. 28, 3219 (1998).

[0494] cis-N-Boc-2,6-dimethylpiperazine was prepared as described in A.Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990).

[0495] 2,6-Difluoro-4-hydroxybenzyl alcohol was prepared according tothe following procedure:

[0496] To a stirred solution of 3,5-difluorophenol (14.5 g) andpotassium hydroxide (85%, 7.4 g) in water (30 mL) at 60° C. was addeddropwise over 1 hour a solution of aqueous formaldehyde (37%, 15.3 mL)in added water (30 mL). The mixture was cooled to 40° C., stirred for 18hours then cooled to 0° C. The mixture was carefully acidified withconc. HCl during which time a white precipitate appeared. The mixturewas stirred for 30 minutes at 0° C. then filtered. The filter-cake waswashed with ice-cold water and dried to give the product as a whitesolid (8.1 g, 46%); δ_(H) (400 MHz, DMSO-d₆) 10.23 (1H, m, OH), 6.44(1H, t, J 4 Hz), 6.39 (1H, t, J 4 Hz), 4.95 (1H, t, J 5.5 Hz, OH) and4.38 (2H, d, J 5.5 Hz); HPLC (XTERRA, MeOH—NH₄OAc, 50%→80%) 94% (0.62min).

[0497] 2-Fluoro-5-hydroxybenzyl alcohol was prepared according to thefollowing procedure: 2-Fluoro-5-hydroxybenzaldehyde: to a stirredsolution of 2-fluoro-5-methoxybenzaldehyde (18.3 g) in dichloromethane(200 mL) at 0° C. was added dropwise a solution of boron tribromide indichloromethane (1M, 120 mL, 1 eq.). The mixture was stirred for 3 hthen concentrated to a volume of ˜50 mL and partitioned between ethylacetate (500 mL) and water (500 mL). The organic layer was washed(water), dried (magnesium sulfate) and concentrated to give a red oil(22.7 g). The oil was purified by column chromatography (SiO₂, DCM→DIPE)to give the product as a pink crystalline solid (9.9 g, 59% yield);

[0498] 2-Fluoro-5-hydroxybenzyl alcohol: to a stirred solution of2-fluoro-5-hydroxybenzaldehyde (4.1 g) in methanol (50 mL) at 0° C. wasadded portionwise sodium borohydride (0.55 g). The mixture was warmed toroom temperature, stirred for 1 hour then partitioned between water (200mL) and ethyl acetate (2×200 mL). The combined organics were washed(brine), dried (magnesium sulfate) and concentrated to give2-fluoro-5-hydroxybenzyl alcohol as a yellow oil which crystallised onstanding overnight (4.1 g, 95% yield):

[0499] Alternatively 2-fluoro-5-hydroxybenzyl alcohol was preparedaccording to the following procedure:

[0500] 2-Fluoro-5-hydroxybenzyl alcohol: to a stirred solution of2-fluoro-5-methoxybenzaldehyde (1.0 g) in toluene (30 ml) at 0° C. underAr was added dropwise a solution of DIBAL-H (1.0 M, toluene, 3.2 ml).The mixture was stirred for 30 min then heated to 100° C. and stirredfor 18 h. The mixture was cooled to 0° C. and quenched by dropwiseaddition of ethyl acetate (5 ml), methanol (2 ml) and water (1 ml). Themixture was stirred for 30 min then partitioned between dil.hydrochloric acid (30 ml) and ethyl acetate (2×30 ml). The combinedorganics were washed (water, brine), dried (sodium sulfate) andconcentrated in vacuo. The residue was triturated with isohexane-DCM(10:1) to give the product as a white solid (0.56 g, 61%): δ_(H) (400MHz, DMSO-d₆) 9.24 (1H, m, OH), 6.90 (1H, dd, J 10, 9 Hz), 6.85 (1H, q,J 3 Hz), 6.60 (1H, m), 5.15 (1H, m, OH) and 4.46 (2H, s); HPLC (XTERRA,20/50, 280 nm) 93% (1.09 min).

[0501] (R)2-Methyl-piperazine, (RS)2-methylpiperazine and(RS)2-ethylpiperazine were loaded onto solid-phase supports using thefollowing procedure:

[0502] A mixture of polystyrene-PEG-hydroxytrityl resin (4 g,NovaBiochem, 0.26 mmol/g loading, 1.04 mmol), freshly distilled acetylchloride (5 mL, 56 mmol) and toluene (50 mL) was heated under reflux for3 h then cooled to room temperature. The resin was filtered off andwashed three times each with toluene, THF, dichloromethane and tolueneagain. The resin was used in the next step immediately.

[0503] To a 20 mL solid-phase tube was added approximately half of theresin from the previous step (2 g, 0.52 mmol)) and dry THF (10 mL). Thetube was shaken for 10 minutes then the solvent was removed by suctionfiltration. More THF (10 mL) and (R)2-methylpiperazine (0.18 g, 1.8mmol) were added and the mixture was sealed and shaken for 18 hours. Thesolvent was removed by suction filtration and the resin was sequentiallywashed three times with THF, methanol, dichloromethane and THF againthen dried under vacuum.

[0504] S-4-hydroxybenzyl piperazine-1-thiocarboxylate was preparedaccording to the following procedure adapted from: M. R. Tremblay et al,Bioorg. Med. Chem., (1999), 7, 1013-1023.

[0505] 4-(tert-butydimethylsilyloxy)-benzaldehyde: to a stirred solutionof 4-hydroxybenzaldehyde (25.0 g, 205 mmol) in dry DMF (200 mL) wasadded imidazole (28.0 g, 410 mmol) and TBDMS-Cl (32.4 g, 215 mmol) underan argon atmosphere. The resulting mixture was stirred for 4 h at roomtemperature (rt) then water was added and the mixture was extracted withether (2×300 mL) and dichloromethane (2×300 mL). The combined organicswere dried (MgSO₄), filtered and concentrated under vacuum. The crudeoil was purified by filtration through silica gel (eluting withhexane—EtOAc, 95:5) to give the product as a colourless oil (48.0 g,99%).

[0506] 4-(tert-Butydimethylsilyloxy)-benzyl alcohol: to a stirredsolution of 4-(tert-butydimethylsilyloxy)-benzaldehyde (48.0 g, 203mmol) in methanol (200 ML) at 0° C. was added sodium borohydride (11.6g, 305 mmol) and the reaction was stirred at 0° C. for 45 min. Water(200 mL) was added and the methanol was removed under reduced pressure.The mixture was extracted with ether (2×200 mL) and ethyl acetate (2×200mL). The combined organics were dried (MgSO₄), filtered and concentratedunder vacuum to give the crude product, which was used without furtherpurification (48 g, quantitative).

[0507] Ethanethioic acid, S-[4-(tert-butyldimethylsilyloxy)benzyl]ester:To an efficiently stirred solution of triphenylphosphine (81 g, 309mmol) in THF (200 mL) was added diethyl azodicarboxylate (62.5 g, 309mmol) at 0° C. The mixture was stirred for 30 min, after which time athick white precipitate was obtained. The crude4-(tert-butydimethylsilyloxy)-benzyl alcohol (48 g) in THF (100 mL) andthiolacetic acid (36.1 g, 474 mmol) were added dropwise while thetemperature was maintained below 10° C. The reaction was stirredovernight while keeping the internal temperature below 10° C. Thesolvent was removed in vacuo and the residue was purified by flashcolumn chromatography [SiO₂: isohexane-ethyl acetate (9:1)] to give theproduct as a viscous brown oil (30.7 g, 50%).

[0508] 4-(tert-Butyldimethylsilyloxy)-benzenemethanethiol: to a stirredsolution of ethanethioic acid,S-[4-(tert-butyldimethylsilyloxy)benzyl]ester (30.7 g, 104 mmol) in dryTHF (300 mL) at 0° C. under an argon atmosphere was added lithiumaluminium hydride (5.9 g, 156 mmol). The reaction was stirred for 3 h at0° C. The mixture was quenched by careful addition of EtOAc then water.The pH was brought to 5 with an aqueous solution of 10% HCl and theresulting slurry was filtered. The filtrate was extracted with EtOAc(2×100 mL) and the combined organic layers were washed successively withRochelle's salt, brine, dried (MgSO₄), filtered and concentrated to givethe product as a green oil (22.1 g, 84%).

[0509] S-4-(tert-butyl-dimethylsilyloxy)benzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate: to a stirred solutionof 4-(tert-butyldimethylsilyloxy)-benzenemethanethiol (10.5 g, 41 mmol)and triethylamine (69 mmol, 9.6 mL) in THF (500 mL) at 0° C. was added4-tert-butoxycarbonyl-1-chlorocarbonylpiperazine (8.56 g, 34 mmol) andDMAP (6.9 mmol, 0.84 g). The reaction mixture was warmed to 50° C. andstirred for 3 h then poured into water (500 mL) and extracted with EtOAc(2×250 mL). The combined organic extracts were washed with water (250mL) then brine (500 mL), then dried (MgSO₄) and concentrated to reveal abrown oil. Chromatography [SiO₂: 90/10, hexane/EtOAc)] gave the productas a yellow oil which crystallised on standing (13.4 g, 85%): m.p.53-54° C. ¹H-NMR (400 MHz, CDCl₃): 0.18 (6H, s), 0.96 (9H, s), 1.46 (9H,s), 3.42-3.51 (8H, m), 4.12 (2H, s), 6.75 (2H, d, J=8.5 Hz) and 7.18(2H, d, J=8.5 Hz).

[0510] S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate: to a stirred solutionof S-4-(tert-butyl-dimethylsilyloxy)benzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (10 g, 22 mmol) in THF(100 mL) was added a solution of TBAF in THF (1 N, 24 mL, 24 mmol). Themixture was stirred at room temperature for 40 min then diluted withwater (200 mL) and extracted with EtOAc (2×250 mL). The combined organicextracts were washed successively with water (250 mL) and brine (500 mL)then dried (MgSO₄), filtered and concentrated to reveal a brown oil.Trituration with EtOAc/hexane afforded the product as a white solid (3.7g, 47%): ¹H-NMR (400 MHz, d₆-DMSO) 9.32 (1H, m), 7.11dt (2H, t, J 8.5,2.5 Hz), 6.67 (2H, t, J 8.5, 2.5 Hz), 4.02 (2H, s), 3.43 (4H, m), 3.33(4H, m) and 1.40 (9H, s).

[0511] All other starting materials and reagents are commerciallyavailable unless otherwise stated.

Example 1

[0512] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl esterhydrochloride

[0513] Piperazine-1,4-dicarboxylic acid tert-butyl ester4-trifluoromethoxy-benzyl ester: 652 mg (1.5 mmol) PS-BEMP and 373 mg(1.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butylester was added to a solution of 192 mg (1.0 mmol)4-trifluoromethoxybenzyl alcohol in 5 ml acetonitrile. The mixture washeated to reflux for 24 h then cooled to rt, diluted with 5 mlacetonitrile, 666 mg (4.5 mmol) PS-NH2 added and shaken at rt for 16 h.After filtration and evaporation the crude product is purified by flashchromatography on silica gel with hexane/AcOEt 50:50:180 mg colourlesscrystalline solid. ¹H-NMR (CDCl₃): 1.45 s, 9H, 3.35-3.55 m, 8H, 5.14 s,2H, 7.20 d, 2H and 7.40 d, 2H, AB-system.

[0514] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl esterhydrochloride: A solution of 174 mg (0.49 mmol)piperazine-1,4-dicarboxylic acid tert-butyl ester4-trifluoromethoxy-benzyl ester in 4.9 ml 1.5M HCl/Et2O and 0.98 ml abs.MeOH was stirred at rt for 3 h. Evaporation of the reaction mixtureprovided 189 mg as colourless powder. ¹H-NMR (d₆-DMSO): 3.10 m, 4H and3.62 m, 4H; 5.13 2, 2H; 7.40 d, 2H and 7.53 d, 2H, AB-system; 9.2 br,2H. MS (ISP): 305.2 (M+H)⁺.

[0515] In analogy to Example 1 the following carbamates of Examples 2-24were prepared from the given starting material that is eithercommercially available or described in the literature:

Example 2

[0516] Piperazine-1-carboxylic acid 3,4-difluoro-benzyl esterhydrochloride was prepared from 3,4-difluorobenzyl alcohol; MS (ISP):257.1 MH⁺.

Example 3

[0517] Piperazine-1-carboxylic acid 4-fluoro-benzyl ester hydrochloridewas prepared from 4-fluorobenzyl alcohol; MS (ISP): 239.3 MH⁺.

Example 4

[0518] Piperazine-1-carboxylic acid 4-bromo-benzyl ester hydrochloridewas prepared from 4-bromobenzyl alcohol; MS (ISP): 299.1 MH⁺.

Example 5

[0519] Piperazine-1-carboxylic acid 2-trifluoromethoxy-benzyl esterhydrochloride was prepared from 2-trifluoromethoxy-benzyl alcohol; MS(ISP): 305.2 MH⁺.

Example 6

[0520] Piperazine-1-carboxylic acid 2-chloro-5-nitro-benzyl esterhydrochloride was prepared from 2-chloro-5-nitro-benzyl alcohol; MS(ISP): 300.3 MH⁺.

Example 7

[0521] Piperazine-1-carboxylic acid 2-chloro-benzyl ester hydrochloridewas prepared from 2-chlorobenzyl alcohol; MS (ISP): 255.1 MH⁺.

Example 8

[0522] Piperazine-1-carboxylic acid biphenyl-4-ylmethyl esterhydrochloride was prepared from 4-biphenylmethanol; MS (ISP): 297.3 MH⁺.

Example 9

[0523] Piperazine-1-carboxylic acid 3-methoxy-benzyl ester hydrochloridewas prepared from 3-methoxybenzyl alcohol; MS (ISP): 250.2 MH⁺.

Example 10

[0524] Piperazine-1-carboxylic acid 3-trifluoromethyl-benzyl esterhydrochloride was prepared from 3-(trifluoromethyl)-benzyl alcohol; MS(ISP): 289.2 MH⁺.

Example 11

[0525] Piperazine-1-carboxylic acid 4-trifluoromethyl-benzyl esterhydrochloride was prepared from 4-(trifluoromethyl)-benzyl alcohol; MS(ISP): 289.1 MH⁺.

Example 12

[0526] Piperazine-1-carboxylic acid naphthalen-2-ylmethyl esterhydrochloride was prepared from 2-naphthalenemethanol; MS (ISP): 271.3MH⁺.

Example 13

[0527] Piperazine-1-carboxylic acid naphthalen-1-ylmethyl esterhydrochloride was prepared from 1-naphthalenemethanol; MS (ISP): 271.3MH⁺.

Example 14

[0528] Piperazine-1-carboxylic acid 2-methyl-benzyl ester hydrochloridewas prepared from 2-methylbenzyl alcohol; MS (ISP): 235.4 MH⁺.

Example 15

[0529] Piperazine-1-carboxylic acid 2,4-dichloro-benzyl esterhydrochloride was prepared from 2,4-dichlorobenzyl alcohol; MS (EI):288.0 M⁺.

Example 16

[0530] Piperazine-1-carboxylic acid 2,6-dichloro-benzyl esterhydrochloride was prepared from 2,6-dichlorobenzyl alcohol; MS (ISP):289.1 MH⁺.

Example 17

[0531] Piperazine-1-carboxylic acid 4-tert-butyl-benzyl esterhydrochloride was prepared from 4-tert.-butyl-benzyl alcohol; MS (ISP):277.3 MH⁺.

Example 18

[0532] Piperazine-1-carboxylic acid 2-fluoro-4-trifluoromethyl-benzylester hydrochloride was prepared from 2-fluoro-4-trifluoromethyl-benzylalcohol; MS (ISP): 307.2 MH⁺.

Example 19

[0533] Piperazine-1-carboxylic acid 2,4-difluoro-benzyl esterhydrochloride was prepared from 2,4-difluorobenzyl alcohol; MS (ISP):257.1 MH⁺.

Example 20

[0534] Piperazine-1-carboxylic acid 2-chloro-4-fluoro-benzyl esterhydrochloride was prepared from 2-chloro-4-fluorobenzyl alcohol; MS(ISP): 273.2 MH⁺.

Example 21

[0535] Piperazine-1-carboxylic acid 4-fluoro-2-trifluoromethyl-benzylester hydrochloride was prepared from 4-fluoro-2-trifluoromethyl-benzylalcohol; MS (ISP): 307.3 MH⁺.

Example 22

[0536] Piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl esterhydrochloride was prepared from 4-difluoromethoxy-benzyl alcohol; MS(ISP): 287.2 MH⁺.

Example 23

[0537] Piperazine-1-carboxylic acid 2,4-dimethyl-benzyl esterhydrochloride was prepared from 2,4-dimethyl-benzyl alcohol; MS (ISP):248.2 MH⁺.

Example 24

[0538] Piperazine-1-carboxylic acid cyclohexylmethyl ester hydrochloridewas prepared from hydroxymethyl-cyclohexane; MS (EI): 226.3 M⁺.

Example 25

[0539] Piperazine-1-carboxylic acid 2-fluoro-benzyl ester hydrochloride:Piperazine-1,4-dicarboxylic acid tert-butyl ester 2-fluoro-benzyl ester:A solution of 4.47 g N-Boc-piperazine in 40 ml acetonitrile wassaturated with dry carbon dioxide gas at rt. To this solution was addeddropwise in 5 min. a solution of 8.50 g (28 mmol) terabutylammoniumhydrogencarbonate (dried at 50° C. at 0.1 mbar for 1 h) in 30 mlacetonitrile, and then carbon dioxide gas bubbled into the stirredsolution at rt for 1 h. Then 2.90 g (20 mmol) 2-fluorobenzyl chloridewas added drop-wise within 5 min. After stirring at rt for 3 h thereaction mixture was evaporated, 150 ml of water added and extractedwith AcOEt. The organic layer was washed with brine, dried over Na₂SO₄and evaporated. Purification by flash chromatography on silica gel withhexane/AcOEt 50:50 provided 4.29 g piperazine-1,4-dicarboxylic acidtert-butyl ester 2-fluoro-benzyl ester as colourless powder.¹H-NMR(CDCl₃): 1.46 s, 9H; 3.35-3.55 m, 8H; 5.21 s, 2H; 7.02-7.20 m, 2Hand 7.27-7.45 m, 2H. MS (EI): 338.1 M⁺.

[0540] Piperazine-1-carboxylic acid 2-fluoro-benzyl esterhydrochloridewas prepared in analogy to Example 1. Colourless powder,¹H-NMR (CDCl₃): 3.18 sbr, 4H and 3.85 sbr, 4H; 5.21 s, 2H; 7.03-7.22 m,2H and 7.30-7.46 m, 2H; 10.1 br, 2H. MS (ISP): 239.3 (M+H)⁺.

[0541] In analogy to Example 25 the carbamates of Examples 26-31 were beprepared from the given starting material that is either commerciallyavailable or described in the literature:

Example 26

[0542] cis-2,6-Dimethyl-piperazine-1-carboxylic acid 4-chloro-benzylester hydrochloride

[0543] Prepared in analogy to Example 25 withcis-N-Boc-2,6-dimethyl-piperazine and 4-chloro-benzyl chloride.Colourless powder, 1H-NMR (d₆-DMSO): 1.30 d 7.2 Hz, 6H; 3.0-3.25 m, 4Hand 4.2-4.4m, 2H; 5.11 s, 2H; 7.35-7.55 AB-system, 4H; 9.5 br, 2H. MS(ISP): 283.1 (M+H)⁺.

Example 27

[0544] cis-2,6-Dimethyl-piperazine-1-carboxylic acid 3-cyano-benzylester was prepared from 1-Boc-cis-3,5-dimethyl-piperazine and3-cyano-benzyl bromide; MS (ISP): 274.3 MH⁺.

Example 28

[0545] cis-2,6-Dimethyl-piperazine-1-carboxylic acid4-methoxycarbonyl-benzyl ester hydrochloride was prepared from1-Boc-cis-3,5-dimethyl-piperazine and methyl 4-(bromomethyl)-benzoate;MS (ISP): 307.3 MH⁺.

Example 29

[0546] Piperazine-1-carboxylic acid 4-cyano-benzyl ester hydrochloridewas prepared from 4-cyano-benzyl bromide; MS (ISP): 246.3 MH⁺.

Example 30

[0547] Piperazine-1-carboxylic acid 2-trifluoromethyl-benzyl esterhydrochloride was prepared from methanesulfonic acid2-trifluoromethyl-benzyl ester that was prepared from2-trifluoromethyl-benzyl alcohol and methanesulfonyl chloride followinga text book procedure; MS (ISP): 289.2 MH⁺.

Example 31

[0548] Piperazine-1-carboxylic acid 4-chloro-2-fluoro-benzyl esterhydrochloride was prepared from 4-chloro-2-fluoro-benzyl bromide; ¹H-NMR(d₆-DMSO): 3.07 m, 4H and 3.59m, 4H, piperazine-H; 5.13 s, 2H, OCH₂; MS(ISP): 273.2 MH⁺.

Example 32

[0549] Piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)esterhydrochloride:4-(4-Benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acidtert-butyl ester: Under argon 84 mg (1.5 mmol) of solid KOH wasdissolved at rt in 214 mg (1 mmol) 4-(benzyloxy)-benzyl alcohol and 0.5ml acetone. Then 76 mg (1.1 mmol) carbon disulfide was added and themixture thoroughly stirred for 2 h. 323 mg (1.3 mmol)4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester was addedand the mixture heated at reflux for 8 h. The reaction mixture wascooled to rt, 3 ml of water added and extracted with TBME. The organicphase was washed with water and brine to pH 7, dried over Na₂SO₄ andevaporated. Purification of the crude product by preparative HPLC on aPRO C18 column with a H₂O/MeCN gradient provided 87 mg4-(4-benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acidtert-butyl ester as colourless powder. ¹H-NMR (CDCl₃): 1.46 s, 9H;3.40-3.65 m, 8H; 4.13 s, 2H; 5.04 s, 2H; 6.90 d, 2H and 7.25-7.48 m, 7H.

[0550] Piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)esterhydrochloride: A solution of 86 mg (0.19 mmol)4-(4-benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acidtert-butyl ester in 2.2 ml 1.5M HCl/Et₂O and 0.45 ml abs. MeOH wasstirred at rt for 4 h. Evaporation of the reaction mixture provided 64mg product as colourless powder. ¹H-NMR(d₆-DMSO): 3.03-3.17 m, 4H and3.58-3.73 m, 4H; 4.09 s, 2H; 5.08 s, 2H; 6.95 d, J=7.5 Hz, 2H and 7.26d, J=7.5 Hz, 2H (AB-system) and 7.30-7.50 m, 5H; 9.2 br, 2H. MS (ISP):343.2 (M+H)⁺.

[0551] In analogy to Example 32 the following thiocarbamates of Examples33-39 were prepared from the given starting material that is eithercommercially available or described in the literature:

Example 33

[0552] Piperazine-1-carbothioic acid S-(4-bromo-benzyl)esterhydrochloride was prepared from 4-bromobenzyl alcohol; ¹H-NMR (d₆-DMSO):3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.12 s, 2H, SCH₂; MS (ISP):317.1 MH⁺.

Example 34

[0553] Piperazine-1-carbothioic acid S-(4-trifluoromethoxy-benzyl)esterhydrochloride was prepared from 4-trifluoromethoxy-benzyl alcohol;¹H-NMR (d₆-DMSO): 3.12 m, 4H and 3.70 m, 4H, piperazine-H; 4.21 s, 2H,SCH₂; MS (ISP): 321.3 MH⁺.

Example 35

[0554] Piperazine-1-carbothioic acid S-(4-fluoro-benzyl)esterhydrochloride was prepared from 4-fluoro-benzyl alcohol; ¹H-NMR(d₆-DMSO): 3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.14 s, 2H, SCH₂; MS(ISP): 255.1 MH⁺.

Example 36

[0555] Piperazine-1-carbothioic acid S-(2,4-difluoro-benzyl)esterhydrochloride was prepared from 2,4-difluoro-benzyl alcohol; ¹H-NMR(d₆-DMSO): 3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.14 s, 2H, SCH₂; MS(ISP): 273.2 MH⁺.

Example 37

[0556] Piperazine-1-carbothioic acid S-(4-methoxy-benzyl)esterhydrochloride was prepared from 4-methoxy-benzyl alcohol; ¹H-NMR(d₆-DMSO): 3.10 m, 4H and 3.67 m, 4H, piperazine-H; 3.72 s, 3H, OCH₃;4.09 s, 2H, SCH₂; MS (ISP): 267.3MH⁺.

Example 38

[0557] Piperazine-1-carbothioic acid S-(2,4-dimethyl-benzyl)esterhydrochloride was prepared from 2,4-dimethylbenzyl alcohol; ¹H-NMR(d₆-DMSO): 2.23 s, 3H, and 2.27 s, 3H, 2×CH₃-aryl; 3.10 m, 4H and 3.66m, 4H, piperazine-H; 4.10 s, 2H, SCH₂; MS (ISP): 265.3 MH⁺.

Example 39

[0558] Piperazine-1-carbothioic acidS-(2-fluoro-4-trifluoromethyl-benzyl)ester hydrochloride was preparedfrom 2-fluoro-4-trifluoromethyl-benzyl alcohol; ¹H-NMR (d₆-DMSO): 3.10m, 4H and 3.67 m, 4H, piperazine-H; 4.24 s, 2H, SCH₂; MS (ISP): 323.3MH⁺.

Example 40

[0559] Piperazine-1-carbothioic acidS-[4-(4-fluoro-benzyloxy)-benzyl]ester hydrochloride:4-(4-Fluoro-benzyloxy)-phenyl-methanethiol in analogy to S. Vetter,Synth. Commun. 28, 3219 (1998): A mixture of 6.00 (26 mmol)4-(4-fluorobenzyloxy)-benzyl alcohol and 3.93 g (52 mmol) thiourea wasdissolved at 50° C. in water/acetone 1:1.5. To this solution 7.75 ml 5NHCl was added dropwise and the mixture stirred at 50° C. for 16 h. Thenthe solution was cooled and extracted quickly twice with Et₂O, theaqueous layer made alkaline by addition of 3.1 g (78 mmol) NaOH pelletsand heated to reflux for 3 h. Acidification of the reaction mixture atrt with 5N HCl, extraction with AcOEt, drying with Na₂SO₄ andevaporation furnished 6.25 g 4-(4-fluoro-benzyloxy)-phenyl-methanethiolas a colourless powder: mp. 77-80° C. ¹H-NMR (d₆-DMSO): 2.77 t, J=7.5Hz, 1H; 3.68 d, J=7.5 Hz, 2H; 5.06 s, 2H; 6.94 d, 2H and 7.18-7.32 m, 4Hand 7.45-7.58 m, 2H.

[0560]4-[4-(4-Fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylicacid tert-butyl ester: 5.84 g (23.5 mmol)4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester wereadded to a solution of 6.0 g (24.2 mmol)4-(4-fluoro-benzyloxy)-phenyl-methanethiol in 14.6 ml pyridine. Thesolution was heated to 100° C. for 3.5 h, then cooled to rt, 10 ml ofwater added and the volume reduced to a third. The resulting precipitateis collected, washed with water and dried. The crude product isre-crystallized from hexane/AcOEt. Flash chromatography on silica gelprovided 4.90 g4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylicacid tert-butyl ester as colourless powder, mp: 123-124° C. 1H-NMR(CDCl₃): 1.46 s, 9H; 3.38-3.60 m, 8H; 4.13 s, 2H; 5.00 s, 2H; 6.89 d,2H, 7.06 t, 2H, 7.28 d, 2H and 7.40 dd, 2H.

[0561] Piperazine-1-carbothioic acidS-[4-(4-fluoro-benzyloxy)-benzyl]ester hydrochloride: A solution of 4.89g (10.6 mmol)4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carboxylicacid tert-butyl ester in 120.6 ml 1.5M HCl/Et₂O and 24.1 ml abs. MeOHwas stirred at rt for 6 h. Evaporation of the reaction mixture provided3.96 g piperazine-1-carbothioic acidS-[4-(4-fluoro-benzyloxy)-benzyl]ester hydrochloride as colourlesspowder, mp. 169-169.5° C. ¹H-NMR(d₆-DMSO): 3.05 m, 4H and 3.58-3.75 m,4H; 4.09 s, 2H; 5.06 s, 2H; 6.94 d, 2H, 7.17-7.30 m, 4H and 7.43-7.55 m,2H; 9.2 br, 2H. MS (ISP): 361.2 (M+H)⁺.

Example 41

[0562] Piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester

[0563] (RS)-Carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester:A solution of 1.07 g (5.0 mmol) 4-benzyloxybenzyl alcohol and 0.786 g(5.5 mmol) 1-chloroethyl chloroformate in 25 ml CH₂Cl₂ is cooled to 0°C. and 0.435 g (5.5 mmol) pyridine added. After stirring at rt for 2 hthe reaction mixture is quenched with 1N HCl, the organic phaseseparated and washed with sat. NaHCO₃ solution and brine, dried overNa₂SO₄ and evaporated: 1.58 g (98%) (RS)-carbonic acid4-benzyloxy-benzyl ester 1-chloro-ethyl ester as light yellow oil.¹H-NMR (CDCl₃): 1.81 d, J=6 Hz, 3H; 5.07 s, 2H; 5.14 and 5.17, AB-systemJ=15 Hz, 2H; 6.43 q, J=6 Hz, 1H; 6.97 d, J=8.5 Hz, 2H and 7.30-7.45 m,7H.

[0564] Piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester9H-fluoren-9-ylmethyl ester: A solution of 1.47 g (4.7 mmol)N-Fmoc-piperazine (obtained from N-Fmoc-piperazine hydrobromide bytreatment with aqueous NaHCO₃ and extraction with TBME, drying theorganic layer over Na₂SO₄ and evaporation under reduced pressure at <30°C.) in 18 ml CH₂Cl₂ at 0° C. was added dropwise to a solution of 1.51 g(4.7 mmol) (RS)-carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethylester in 57 ml of CH₂Cl₂ . The reaction is slightly exothermic and acolourless precipitate is formed. After 1 h at 0° C. the mixture wasallowed to warm to rt and stirred for further 62 h. Then the reaction isquenched with 2.35 ml 4M K₂CO₃, filtered over a plug of Na₂SO₄ andevaporated. The crude product (2.67 g) was purified byflash-chromatography on silica gel with hexane/AcOEt 50:50 as eluent:1.54 g (60%) RO-72-0160/000 as yellow solid. IR (Nujol): 1699 cm⁻¹.¹H-NMR (CDCl₃): 3.25-3.60 br, 8H; 4.23 t, J=6.4 Hz, 1H; 4.48 d, J=6.4Hz, 2H; 5.06 s and 5.07 s, 4H; 6.97 d, J=8.4 Hz, 2H, 7.26-7.45, m 11H,7.55 d, J=7.6 Hz, 2H and 7.76 d, J=7.6 Hz, 2H. MS (ISP): 566.4 (M+NH₄)⁺;571.4 (M+Na)⁺.

[0565] Piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester: A solutionof 274 mg (0.5 mmol) piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzylester 9H-fluoren-9-ylmethyl ester in 13 ml morpholine was stirred at rtfor 1 h. Then 23 ml of chilled water was added, the suspension filteredand the filtrate extracted with TBME. The organic layer was washed withwater, brine, dried over Na₂SO₄ and evaporated: 54 mgpiperazine-1-carboxylic acid 4-benzyloxy-benzyl ester as light yellow,waxy solid. MIR: 3300 cm⁻¹, 1688 cm⁻¹. ¹H-NMR (CDCl₃): 1.77 br, 1H;2.75-2.90 m, 4H and 3.40-3.50 m, 4H; 5.06 s and 5.07 s, 4H; 6.96 d,J=8.8 Hz, 2H and 7.28-7.44 m, 7H. MS (ISP): 327.3 (M+H)⁺.

[0566] In analogy to Example 41 the following carbamates of Examples42-45 were prepared from the given starting material that is eithercommercially available or described in the literature.

Example 42

[0567] Piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl ester(RS)-Carbonic acid 1-chloro-ethyl ester 4-(4-fluoro-benzyloxy)-benzylester: Prepared in analogy to (RS)-carbonic acid 4-benzyloxy-benzylester 1-chloro-ethyl ester (Example 41) from4-(4-fluoro-benzyloxy)-benzyl alcohol and 1-chloroethyl chloroformate:light yellow oil. ¹H-NMR (CDCl₃): 1.81 d, J=5.5 Hz, 3H; 5.03 s, 2H; 5.13and 5,18 J=5.5 Hz, AB-system, 2H; 6.43 q, 1H; 6.95 d, J=8.4 Hz, 2H, 7.07t J=8.4 Hz, 2H, 7.28-7.45 m, 4H.

[0568] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester4-(4-fluoro-benzyloxy)-benzyl ester: Prepared in analogy topiperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester9H-fluoren-9-ylmethyl ester (Example 41) from (RS)-carbonic acid1-chloro-ethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester) andN-Fmoc-piperazine: yellow solid. ¹H-NMR (CDCl₃): 3.3-3.6 m, 8H; 4.23 t,J=6 Hz, 1 H; 4.48 d, J=6 Hz, 2H; 5.03 s, 2H; 5.08 s, 2H; 6.95 d, J=8.5Hz, 2H, 7.08 t, J=8.5 Hz, 2H, 7.25-7.46 m, 8H, 7.55 d, J=7 Hz, 2H and7.77 d, J=7 Hz, 2H.

[0569] Piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl ester:Prepared in analogy to piperazine-1-carboxylic acid 4-benzyloxy-benzylester (Example 41) from piperazine-1,4-dicarboxylic acid9H-fluoren-9-ylmethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester andmorpholine: colourless, waxy solid: IR (Nujol): 3341 cm⁻¹, 1689 cm⁻¹.¹H-NMR (CDCl₃): 1.75 br, 1H; 2.85-2.90 m, 4H and 3.40-3.55 m, 4H; 5.02s, 2H; 5.07 s, 2H; 6.94 d, J=8.4 Hz, 2H, 7.07 t, J=8.8 Hz, 2H, 7.30 d,J=8.4 Hz, 2H and 7.38-7.42 m, 2H. MS (EI): 344.3 M⁺.

Example 43

[0570] Piperazine-1-carboxylic acid 4-methoxy-benzyl ester hydrochloridewas prepared from 4-methoxy-benzyl alcohol via the FollowingIntermediates

[0571] (RS)-Carbonic acid 1-chloro-ethyl ester 4-methoxy-benzyl ester:¹H-NMR (CDCl₃): 1.81 d, J=8.2 Hz, 3H; 3.81 s, 3H; 5.14 and 5.18AB-system, J=16 Hz, 2H; 6.42 1, J=8.2 Hz, 1H; 6.90 d, J=8 Hz, 2H and7.36 d, J=8 Hz, 2H. MS (EI): 244.1 M⁺.

[0572] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester4-methoxy-benzyl ester: ¹H-NMR (CDCl₃): 3.32-3.58 br, 8H; 3,81 s, 3H;4.24 t, J=6 Hz, 1H; 4.58 d, J=6 Hz, 2H; 5.07 s, 2H; 6.92 d, J=8 Hz, 2H,7.54-7.46 m, 6H, 7.54 d, J=8 Hz, 2H, 7.78 d, J=8 Hz, 2H.

[0573] Piperazine-1-carboxylic acid 4-methoxy-benzyl esterhydrochloride: Deprotection with morpholine led topiperazine-1-carboxylic acid 4-methoxy-benzyl ester. The hydrochloridewas prepared by addition of HCl/Et₂O to a solution of the free base inEt₂O followed by evaporation. ¹H-NMR (d6-DMSO): 3.10 m, 4H and 3.60 m,4H, piperazine-H; 5.02 s, 2H. MS (ISP): 251.2 MH⁺.

Example 44

[0574] Piperazine-1-carboxylic acid benzhydryl ester was Prepared fromdiphenyl carbinol via he Following Intermediates

[0575] (RS)-Carbonic acid benzhydryl ester 1-chloro-ethyl ester: ¹H-NMR(CDCl₃): 1.83 d, J=5.8 Hz, 3H; 6.41 q, J=5.8 Hz, 1H; 6.75 s, 1H;7.25-7.43 m, 10H.

[0576] Piperazine-1,4-dicarboxylic acid benzhydryl ester9H-fluoren-9-ylmethyl ester: ¹H-NMR (CDCl₃): 3.32-3.68 br, 8H; 4.24 t,J=6 Hz, 1H; 4.48 d, J=6 Hz, 2H; 6.82 s, 1H; 7.25-7.44 m, 14H and 7.56 d,J=8 Hz, 2H and 7.78 d, J=8 Hz, 2H.

[0577] Piperazine-1-carboxylic acid benzhydryl ester: ¹H-NMR (CDCl₃):1.70 br, 1H; 2.80-2.85 m, 4H and 3.40-3.70 m, 4H, piperazine-H; 6.82 s,1H; 7.25-7.35 m, 10H. MS (ISP): 297.3 MH⁺.

Example 45

[0578] (RS)-Piperazine-1-carboxylic acid 1-phenyl-ethyl ester wasPrepared from (RS)-1-phenylethanol via the Following Intermediates

[0579] (RS)-Carbonic acid 1-chloro-ethyl ester 1-phenyl-ethyl ester:¹H-NMR (CDCl₃): 1.62 d, J=6.5 Hz and 1.64 d, J=6.5 Hz, 3H; 1.79 d, J=5.8Hz and 1.64 d, J=5.8 Hz, 3H; 5.77 q, J=6.5 Hz and 5.80 q, J=6.5 Hz, 1H;6.37 q, J=5.8 Hz and 6.41 q, J=5.8 Hz, 1H; 7.37 m, 5H.

[0580] (RS)-Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester1-phenyl-ethyl ester: ¹H-NMR (CDCl₃): 1.56 d, J=6.5 Hz, 3H; 3.32-3.58br, 8H; 4.24 t, J=6 Hz, 1H; 4.68 d, J=6 Hz, 2H; 5.83 d, J=6.5 Hz, 1H;7.25-7.44 m, 9H and 7.56 d, J=8 Hz, 2H and 7.78 d, J=8 Hz, 2H.

[0581] (RS)-Piperazine-1-carboxylic acid 1-phenyl-ethyl ester: ¹H-NMR(CDCl₃): 1.54 d, J=4 Hz, 3H; 1.68 br, 1H; 2.75-2.85 m, 4H and 3.40-3.55m, 4H, piperazine-H; 5.82 q, J=4 Hz, 1H; 7.25-7.38 m, 5H. MS (EI): 234.2M⁺.

Example 46

[0582] Piperazine-1-carboxylic acid phenethyl ester

[0583] Phenethyl alcohol (2 eq), triethylamine (3 eq) and pyridine (1eq) was added to a solution of 4-chlorocarbonyl-piperazine-1-carboxylicacid tert-butyl ester in dichloromethane (30 vol.) and the mixture wasshaken at 25° C. for 6 days. The mixture was evaporated, and theresultant crude material purified by preparative HPLC [C18, 10 mMaqueous NH₄OAc solution:MeOH] to afford the intermediate product, whichwas used immediately in the next step.

[0584] A solution of HCl in dioxane (4 M, 10 eq) was added to a solutionof the above intermediate in methanol (50 volumes) and the mixture wasshaken for 16 h. Evaporation to dryness afforded the desired product.

[0585]¹H-NMR (400 MHz, d₆-DMSO): 2.90 (2H, t, J=6.5 Hz), 2.99-3.06 (4H,m), 3.52-3.59 (4H, m), 4.22 (2H, t, J=6.5 Hz), 7.19-7.34 (5H, m) and9.29-9.43 (2H, br s); HPLC: [XTERRA; methanol-10 mM aqueous NH₄OAc(40:60); 2 mL/min; 210 nm] 100% (0.98 min).

Example 47

[0586] cis-2,6-Dimethylpiperazine-1-carboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate

[0587] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid5-(2-chloropyridyl)-methyl ester tert-butyl ester: A solution of2-chloro-5-(hydroxymethyl)pyridine (2.6 g, 18 mmol),1-tert-butoxycarbonyl-2,6-dimethyl-4-chlorocarbonylpiperazine (3.8 g, 14mmol), pyridine (1.5 mL, 19 mmol) and triethylamine (7.6 mL, 52 mmol) indichloromethane (100 mL) was stirred for 96 h. The mixture wasconcentrated in vacuo then partitioned between water (100 mL) and ethylacetate (3×50 mL). The combined organic extracts were washed with waterand brine, then dried over sodium sulfate, concentrated in vacuo andpurified by flash column chromatography [SiO₂; isohexane—ethyl acetate(4:1)] to give the product as a white solid (1.7 g, 32%), m.p. 75-76° C.¹H-NMR (400 MHz, CDCl₃): 8.40 (1H, d, J=2.5 Hz), 7.67 (1H, dd, J=2.5, 8Hz), 7.33 (1H, d, J=8 Hz), 5.14 (2H, s), 4.23-4.14 (2H, m), 4.04-3.82(2H, m), 3.04-2.86 (2H, m), 1.47 (9H, s) and 1.23 (6H, d, J=7 Hz).

[0588] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester:Tris-[2-(2-methoxyethoxy)ethyl]amine (0.02 g, 0.007 mmol) was added to astirred mixture of cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid5-(2-chloropyridyl)methyl ester tert-butyl ester(0.25 g, 0.7 mmol),3-chlorobenzyl alcohol (0.14 g, 1.0 mmol), potassium carbonate (0.09 g,0.7 mmol) and powdered potassium hydroxide (85%, 0.17 g, 2.6 mmol) intoluene (10 mL). The mixture was heated to 120° C., stirred for 4 h,cooled to room temperature, poured into water (20 mL) and extracted withether (3×30 mL). The combined organic extracts were washed with waterand brine, then dried over sodium sulfate, concentrated in vacuo andpurified by flash column chromatography [SiO₂; isohexane—ethyl acetate(9:1) to (3:1)] to give the product as a viscous oil (0.13 g, 40%).¹H-NMR (400 MHz, CDCl₃): 8.16 (1H, d, J=2.5 Hz), 7.63 (1H, dd, J=2.5,8.5 Hz), 7.45 (1H, s), 7.34-7.27 (3H, m), 6.81 (1H, d, J=8.5 Hz), 5.36(2H, s), 5.08 (2H, s), 4.22-4.14 (2H, m), 4.05-3.80 (2H, m), 3.08-2.84(2H, m), 1.47 (9H, s) and 1.22 (6H, d, J=7 Hz); HPLC [Xterra, 2.0mL/min; methanol-10 mM aqueous ammonium acetate solution (50:50) to(80:20) over 5 min then (80:20)] 97% (7.81 min).

[0589] cis-2,6-Dimethylpiperazine-1-carboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate: a solution ofhydrogen chloride in dioxan (4 M, 0.61 mL, 2.4 mmol) was added drop-wiseto a stirred solution of cis-2,6-Dimethylpiperazine-1,4-dicarboxylicacid 5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester(0.12 g, 0.24 mmol) in methanol (5 mL). The mixture was stirred for 18 hthen concentrated in vacuo. The residue was partitioned between ether(2×10 mL) and aqueous sodium hydroxide solution (2 M, 10 mL). Thecombined organic layers were washed with water and brine then dried oversodium sulfate, concentrated in vacuo, dissolved in warm 2-propanol (1mL) and added drop-wise to a stirred solution of fumaric acid (0.033 g,0.28 mmol) in warm 2-propanol (1 mL). The mixture was cooled to 0° C.,stirred for 30 min then filtered. The filter-cake was washed with2-propanol and ether then dried in vacuo to give the product as a whitesolid (0.071 g, 57%), m.p. 172° C. (dec.). ¹H-NMR (400 MHz, d₆-DMSO):8.18 (1H, d, J=2.5 Hz), 7.76 (1H, dd, J=2.5, 8.5 Hz), 7.50 (1H, s),7.42-7.36 (3H, m), 6.93 (1H, d, J=8.5 Hz), 6.59 (2H, s), 5.37 (2H, s),5.04 (2H, s), 4.01-3.93 (2H, m), 2.77 (2H, d, J=12 Hz), 2.70 (2H, dd, J4, 12 Hz) and 1.18 (6H, d, J=7 Hz).

Example 48

[0590] Piperazine-1-carboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate

[0591] 6-(3-Chlorobenzyloxy)nicotinic acid: 6-chloronicotinic acid (1.0g, 6.3 mmol)) was added portion-wise over 30 min to a stirred suspensionof sodium hydride (60%, 0.76 g, 19 mmol) in toluene (10 mL. The mixturewas stirred for 30 min then cooled to 0° C. A solution of3-chloro-benzyl alcohol (0.69 g, 6.4 mmol) in toluene (5 mL) was addeddrop-wise over 10 min. The mixture was warmed to room temperature, DMF(20 mL) was added and the mixture was heated to 95° C. and stirred for18 h. The mixture was cooled to room temperature then poured into water(30 mL). The aqueous mixture was acidified to pH 2 and extracted withethyl acetate (2×30 mL). The combined organic extracts were washed withwater and brine, then dried over sodium sulfate and concentrated invacuo to give a yellow solid (2.36 g). The residue was re-crystallised[2-propanol-water, (2:1)] to give the product as a white solid (0.85 g,51%), m.p. 158° C. (dec.). ¹H-NMR (400 MHz, CDCl₃): 8.93 (1H, d, J=2.5Hz), 8.24 (1H, dd, J=2.5, 8.5 Hz), 7.46 (1H, s), 7.35-7.29 (3H, m), 6.87(1H, dd, J=1, 8.5 Hz) and 5.45 (2H, s).

[0592] 2-(3-Chlorobenzyloxy)-5-(hydroxymethyl)pyridine:6-(3-chlorobenzyloxy)nicotinic acid (0.60 g, 2.3 mmol)was addedportionwise to a stirred suspension of lithium aluminium hydride (0.14g, 3.7 mmol) in THF (10 mL) at 0° C. under Ar. The mixture was warmed toroom temperature, stirred for 2 h then cooled to 0° C. Saturated aqueoussodium potassium tartrate solution (1 mL) was added dropwise followed bysodium sulfate decahydrate (2 g). The mixture was diluted with ether (30mL), stirred for 1 h then filtered through kieselguhr. The filter-cakewas washed with ether (10 mL); the combined filtrates were concentratedin vacuo and purified by flash column chromatography [SiO₂;isohexane—ethyl acetate (4:1) to (1:1)] to give the product as a viscousoil (0.25 g, 44%). ¹H-NMR (400 MHz, CDCl₃): 8.11 (1H, d, J=2.5 Hz), 7.63(1H, dd, J=2.5, 8.5 Hz), 7.45 (1H, s), 7.33-7.25 (3H, m), 6.82 (1H, d,J=8.5 Hz), 5.35 (2H, s), 4.62 (2H, d, J=4 Hz) and 1.87 (1H, t, J=4 Hz,—OH). HPLC: [Xterra, 2.0 mL/min; methanol-10 mM aqueous ammonium acetatesolution (50:50) to (80:20) over 5 min then (80:20)] 98% (3.95 min).

[0593] Piperazine-1,4-dicarboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester: asolution of 2-(3-chlorobenzyloxy)-5-(hydroxymethyl)pyridine (0.22 g, 0.9mmol) in DMF (1 mL) was added drop-wise to a stirred suspension ofsodium hydride (60%, 0.042 g, 1.1 mmol) in DMF (2 mL). The mixture wasstirred for 30 min then a solution of1-tert-butoxycarbonyl-4-chlorocarbonylpiperazine (0.22 g, 0.9 mmol) inDMF (1 mL) was added. The mixture was stirred for 18 h then poured intowater (10 mL) and extracted with ether (2×10 mL). The combined organicextracts were washed with water and brine, then dried over sodiumsulfate, concentrated in vacuo and purified by flash columnchromatography [SiO₂; isohexane—ethyl acetate (9:1) to (3:1)] to givethe product as a viscous oil (0.17 g, 41%). ¹H-NMR (400 MHz, CDCl₃):8.16 (1H, d, J=2.5 Hz), 7.63 (1H, dd, J=2.5, 8.5 Hz), 7.45 (1H, s),7.34-7.26 (3H, m), 6.81 (1H, d, J=8.5 Hz), 5.36 (2H, s), 5.08 (2H, s),3.48-3.36 (8H, m) and 1.46 (9H, s). HPLC: [Xterra, 2.0 mL/min;methanol-10 mM aqueous ammonium acetate solution (50:50) to (80:20) over5 min then (80:20)] 97% (7.35 min).

[0594] Piperazine-1-carboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate: a solution ofhydrogen chloride in dioxan (4 M, 0.9 mL, 3.6 mmol) was added drop-wiseto a stirred solution of Piperazine-1,4-dicarboxylic acid5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester (0.16 g,0.35 mmol) in methanol (5 mL). The mixture was stirred for 18 h thenconcentrated in vacuo. The residue was partitioned between ether (2×10mL) and aqueous sodium hydroxide solution (2 M, 10 mL). The combinedorganic layers were washed with water and brine then dried over sodiumsulfate, concentrated in vacuo, dissolved in warm 2-propanol (2 mL) andadded dropwise to a stirred solution of fumaric acid (0.047 g, 0.41mmol) in warm 2-propanol (2 mL). The mixture was cooled to 0° C.,stirred for 30 min then filtered. The filter-cake was washed with2-propanol and ether then dried in vacuo to give the product as a whitesolid (0.089 g, 54%), m.p. 148° C. (dec.). ¹H-NMR (400 MHz, d₆-DMSO):8.19 (1H, d, J=2.5 Hz), 7.77 (1H, dd, J=2.5, 8.5 Hz), 7.50 (1H, s),7.42-7.36 (3H, m), 6.92 (1H, d, J=8.5 Hz), 6.52 (2H, s), 5.36 (2H, s),5.04 (2H, s), 3.45-3.40 (4H, m) and 2.86-2.80 (4H, m).

Example 49

[0595] cis-2,6-Dimethylpiperazine-1-carboxylic acid 2-(2-thienyl)ethylester

[0596] 2-(2-thienyl)ethanol (2 eq), triethylamine (3 eq) and pyridine (1eq) was added to a solution ofcis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester in dichloromethane (30 vol.) and the mixture was shakenat 25° C. for 6 days. The mixture was evaporated, and the resultantcrude material purified by preparative HPLC [C18, 10 mM aqueous NH₄OAcsolution:MeOH] to afford the intermediate product, which was usedimmediately in the next step.

[0597] A solution of HCl in dioxane (4 M, 10 eq) was added to a solutionof the above intermediate in methanol (50 volumes) and the mixture wasshaken for 16 h. Evaporation to dryness afforded the desired product.HPLC: [XTERRA; methanol-10 mM aqueous NH₄OAc (60:40); 2 mL/min; 210 nm]94.5% (0.83 min); MS(ISP): 269 MH⁺.

[0598] cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester was prepared in analogy to4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester fromcis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (A.Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by a modifiedprocedure of Rhone-Poulenc DE 25 50 111 (Rhone-Poulenc).

Example 50

[0599] cis-2,6-Dimethylpiperazine-1-carboxylic acid 2-fluorobenzyl ester

[0600] 2-fluorobenzyl alcohol (2 eq), triethylamine (3 eq) and pyridine(1 eq) was added to a solution ofcis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester in dichloromethane (30 vol.) and the mixture was shakenat 25° C. for 6 days. The mixture was evaporated, and the resultantcrude material purified by preparative HPLC [C18, 10 mM aqueous NH₄OAcsolution:MeOH] to afford the intermediate product, which was usedimmediately in the next step.

[0601] A solution of HCl in dioxane (4 M, 10 eq) was added to a solutionof the above intermediate in methanol (50 volumes) and the mixture wasshaken for 16 h. Evaporation to dryness afforded the desired product.HPLC: [XTERRA; methanol-10 mM aqueous NH₄OAc (60:40); 2 mL/min; 210 nm]96.8% (0.88 min); MS (ISP): 267 MH⁺.

[0602] cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acidtert-butyl ester was prepared in analogy to4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester fromcis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (A.Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by a modifiedprocedure of Rhone-Poulenc DE 25 50 111 (Rhone-Poulenc).

Example 51

[0603] Piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzylester

[0604] Piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzylester: A mixture[(4-tert-butyl-dimethylsilyloxy)benzylsulfanylcarbonyl]-piperazine-4-carboxylicacid tert-butyl ester (0.05 g), 3-nitrobenzyl bromide (0.028 g), cesiumfluoride (0.033 g) and DMF (1 mL) was shaken for 48 h then partitionedbetween water (2 mL) and dichloromethane (2 mL). The separated organiclayer was concentrated in vacuo then suspended in trifluoroaceticacid—dichloromethane (1:1, 1 mL) and shaken for 18 h. The mixture wasconcentrated in vacuo and purified by preparative HPLC [C1 8, 10 mMaqueous NH₄OAc solution: MeOH] to afford the product (0.011 g, 25%).HPLC: [Xterra, 2.0 mL/min; methanol-10 mM aqueous ammonium acetatesolution (50:50) to (80:20) over 5 min then (80:20)] 98% (5.1 min); MS(ISP): 387 MH⁺.

Example 52

[0605] Piperazine-1-carboxylic acid 3-(2-phenylethoxy)-benzyl esterhydrochloride

[0606] Piperazine-1,4-dicarboxylic acid(3-tert-butyldimethylsilyloxy)benzyl ester tert-butyl ester: A solutionof 3-tert-butyldimethylsilyloxybenzyl alcohol (Tetrahedron Lett. 26, 681(1985)) (5.0 g), triethylamine (8.7 mL), pyridine (1.65 mL) and4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester (5.1 g)in dichloromethane (200 mL) was stirred for 96 h.4-Dimethylaminopyridine (0.20 g) was added and the mixture was heated toreflux for 4 h. The mixture was cooled to room temperature, washed withwater (100 mL), brine (100 mL), dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatography[SiO₂; dichloromethane, isopropyl ether: (100:0) to (80:20)] to give theproduct as a yellow oil (3.8 g, 41%). ¹H-NMR (400 MHz, CDCl₃): 0.19 (6H,s), 0.98 (9H, s), 1.46 (9H, s), 3.36-3.43 (4H, m), 3.44-3.50 (4H, m),5.08 (2H, s), 6.78 (1H, dd, J=2.5, 8 Hz), 6.82 (1H, t, J=2 Hz), 6.92(1H, d, J=8 Hz) and 7.20 (1H, t, J=8 Hz).

[0607] Piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl estertert-butyl ester: a solution of tetrabutylammonium fluoride in THF (1 M,4.4 mL, 4.4 mmol) and glacial acetic acid (0.76 mL, 13.3 mmol) wereadded sequentially to a stirred solution of piperazine-1,4-dicarboxylicacid (3-tert-butyldimethylsilyloxy)benzyl ester tert-butyl ester (0.50g, 1.1 mmol) in anhydrous THF (10 mL) at 0° C . The mixture was stirredfor 1 h then poured into water (40 mL) and extracted with ethyl acetate(3×20 mL). The combined organic extracts were washed with water (3×25mL), saturated aqueous sodium hydrogencarbonate solution (25 mL) andbrine (25 mL) then dried over magnesium sulfate and concentrated invacuo to give the product as a colourless oil which solidified onstanding (0.38 g, 100%). ¹H-NMR (400 MHz, CDCl₃): 1.46 (9H, s),3.38-3.44 (4H, m), 3.45-3.50 (4H, m), 5.09 (2H, s), 6.79 (1H, dd, J 2.5,8 Hz), 6.83 (1H, m, OH), 6.90 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz) and7.26 (1H, s). HPLC [Xterra, 2.0 mL/min; methanol-10 mM aqueous ammoniumacetate solution (50:50) to (80:20) over 5 min then (80:20)] 100% (3.59min).

[0608] Piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl estertert-butyl ester: potassium carbonate (0.072 g, 0.52 mmol) was added toa solution of piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl estertert-butyl ester (0.16 g, 0.48 mmol) in acetone (5 mL) at 0° C. and thereaction mixture was stirred at 0° C. for 30 min. (2-Bromoethyl)-benzene(0.097 g, 0.52 mmol) was added and the reaction mixture was allowed towarm to room temperature and then heated under reflux for 24 h. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas partitioned between water (20 mL) and ethyl acetate (20 mL). Theorganic phase was separated, washed with saturated brine (25 mL), dried(MgSO₄) and concentrated in vacuo to give an oil which was purified bycolumn chromatography [SiO₂; heptane-ethyl acetate (3:1)] to yield thetitle compound (0.10 g, 48%) as a colourless oil. ¹H-NMR (400 MHz,CDCl₃): 1.46 (9H, s), 3.10 (2H, t, J=7.0 Hz), 3.40 (4H, m), 3.46 (4H,m), 4.18 (2H, t, J=7.0 Hz), 5.09 (2H, s), 6.84 (1H, m), 6.88 (1H, m),6.91 (1H, m) and 7.22-7.34 (6H, m).

[0609] Piperazine-1-carboxylic acid 3-(2-phenylethoxy)-benzyl esterhydrochloride: 4M HCl in 1,4-dioxane (2.3 mL, 9.2 mmol) was added to asolution of piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzylester tert-butyl ester (0.10 g, 0.23 mmol) in methanol (2 mL) and ether(2 mL) and the solution was left to stand with occasional swirling atroom temperature for 3 h. The solution was concentrated in vacuo and theresidue was triturated with ether to yield the title compound (0.08 g,93%) as a white solid. ¹H-NMR (400 MHz, d₆-DMSO): 3.03 (2H, t, J=6.8Hz), 3.08 (4H, m), 3.61 (4H, m), 4.19 (2H, t, J=7.0 Hz), 5.06 (2H, s),6.88-6.94 (3H, m), 7.20-7.33 (6H, m) and 9.19 (2H, br s).

Example 53

[0610]3-[2-(3-Chlorophenyl)ethyl]oxybenzylpiperazine-1-carboxylatehydrochloride

[0611]3-[2-(3-Chlorophenyl)ethyl]oxybenzyl-4-tert-butoxycarbonylpiperazine-1-carboxylatewas prepared from piperazine-1,4-dicarboxylic acid (3-hydroxy)benzylester tert-butyl ester and (2-bromoethyl)-3-chlorobenzene using themethod described for Example 52 to yield the product (0.24 g, 85%) as acolourless oil; ¹H NMR (400 MHz, CDCl₃) 1.46 (9H, s), 3.25 (2H, t, J 7.0Hz), 3.41 (4H, m), 3.46 (4H, m), 4.20 (2H, t, J 7.0 Hz), 5.10 (2H, s),6.84 (1H, m), 6.88 (1H, m), 6.92 (1H, m), 7.14-7.24 (3H, m) and7.28-7.36 (2H, m); HPLC retention time 8.12 min (λ=220 nm).

[0612] 3-[2-(3-Chlorophenyl)ethyl]oxybenzylpiperazine-1-carboxylatehydrochloride was prepared from3-[2-(3-chlorophenyl)ethyl]oxybenzyl-4-tert-butoxycarbonylpiperazine-1-carboxylateusing the method described for Example 52 to yield the title compound(0.14 g, 67%) as a white solid; ¹H NMR (400 MHz, d₆-DMSO) 3.05 (2H, t, J7.0 Hz), 3.08 (4H, m), 3.62 (4H, m), 4.20 (2H, t, J 6.5 Hz), 5.06 (2H,s), 6.88-6.95 (3H, m), 7.25-7.35 (4H, m), 7.42 (1H, m) and 9.20 (2H, brs); HPLC retention time 5.67 min (λ=220 nm).

Example 54

[0613] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester hemifumarate

[0614] 6-(2-Fluorobenzyloxy)nicotinic acid: to a stirred suspension ofsodium hydride (60%, 0.63 g) in DMF (10 ml) at 0° C. was addedportionwise over 10 min 6-chloronicotinic acid (1.0 g). The mixture wasstirred for 30 min then a solution of 2-fluorobenzyl alcohol (0.84 g) inDMF (5 ml) was added dropwise over 10 min. The mixture was warmed toroom temperature, stirred for 1 h then heated to 100° C. and stirred fora further 18 h then cooled to room temperature. To the mixture wereadded dropwise water (10 ml) and hydrochloric acid (2M, 10 ml). Theemerging precipitate was washed with water and dried to give the productas an off-white solid (1.34 g); ¹H-NMR (400 MHz, CDCl₃) δ_(H) 8.75 (1H,dd, J 2.5, 1 Hz), 8.17 (1H, dd, J 8.5, 2.5 Hz), 7.56 (1H, dt, J 7.5, 1.5Hz), 7.43 (1H, m), 7.27 (1H, dd, J 8.5, 1 Hz), 7.22 (1H, dd, J 7.5, 1Hz), 6.97 (1H, dd, J 8.5, 1 Hz) and 5.48 (2H, s); [XTERRA; methanol-10mM aqueous NH₄OAc (50:50); 2 mL/min; 220 nm] 98%, 0.80 min.

[0615] 2-(2-Fluorobenzyloxy)-5-pyridylmethanol: to a stirred solution of6-(2-fluorobenzyloxy)nicotinic acid (0.89 g) in THF (10 ml) at 0° C.under Ar was addded dropwise a solution of lithium aluminium hydride(1.0 M, 5.5 ml). The mixture was warmed to room temperature and stirredfor 2 h. Saturated potassium sodium tartrate solution (1 ml) was addedto the mixture followed by ethyl acetate (10 ml). The mixture wasstirred for 30 min, filtered and concentrated in vacuo to give theproduct as a clear oil (0.63 g) which was used without furtherpurification; δ_(H) (400 MHz, CDCl₃) 8.14 (1H, d, J 1.5 Hz), 7.63 (1H,dd, J 8.5, 2.5 Hz), 7.49 (1H, dt, J 7.5, 1 Hz), 7.29 (1H, m), 7.13 (1H,dt, J 7.5, 1 Hz), 7.02 (1H, dt, J 10, 1 Hz), 6.81 (1H, d, J 8 Hz), 5.45(2H, s) and 4.63 (2H, s); LC 73 %, 2.24 min.

[0616] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester: to a stirred suspensionof sodium hydride (0.084 g) in DMF (2 ml) was added dropwise a solutionof 2-(2-fluorobenzyloxy)-5-pyridylmethanol (0.41 g) and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.45 g)in DMF (4 ml). The mixture was stirred for 18 h then poured into water(20 ml). The aqueous layer was extracted with two portions of ethylacetate (20 ml). The combined organic extracts were washed (water,brine), dried (sodium sulfate) and concentrated in vacuo. The residuewas purified by flash column chromatography [SiO₂; toluene—ether (4:1)]to give the product as a pale oil (0.28 g); 1H-NMR (400 MHz, CDCl₃)δ_(H) 8.19 (1H, d, J 2 Hz), 7.62 (1H, dd, J 8.5, 2.5 Hz), 7.50 (1H, dt,J 7.5, 1.5 Hz), 7.30 (1H, m), 7.14 (1H, dt, J 7.5, 1 Hz), 7.08 (1H, ddd,J 10, 8.5, 1.5 Hz), 6.80 (1H, d, J 8.5 Hz), 5.45 (2H, s), 5.09 (2H, s),4.20 (2H, m), 4.05-3.80 (2H, m), 3.10-2.80 (2H, m), 1.48 (9H, s) and1.22 (6H, d, J 6.5 Hz); HPLC [XTERRA; methanol-10 mM aqueous NH₄OAc(50:50); 2 mL/min; 220 nm] 98%, 7.24 min.

[0617] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester hemifumarate:cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester (0.25 g) and HCl-dioxane(4M, 0.6 ml) were combined as described below for Example 58 to give theproduct as a white solid (0.18 g); ¹H-NMR (400 MHz, DMSO-d₆) 8.20 (1H,d, J 2 Hz), 7.75 (1H, d, J 8.5, 2.5 Hz), 7.53 (1H, dt, J 7.5, 1.5 Hz),7.40 (1H, dddd, J 9, 7.5, 5.5, 1.5 Hz), 7.25 (1H, dd, J 9.5, 1 Hz), 7.20(1H, dd, J 7.5, 1 Hz), 6.89 (1H, d, J 8.5 Hz), 6.57 (1H, s), 5.40 (2H,s), 5.04 (2H, s), 3.95 (2H, m), 2.74 (2H, d, J 12 Hz), 2.68 (2H, dd, J12, 4.5 Hz) and 1.18 (6H, d, J 7 Hz); HPLC [XTERRA; methanol-10 mMaqueous NH₄OAc (50:50); 2 mL/min; 220 nm] 99%, 4.23 min.

Example 55

[0618] 4-Bromo-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was synthesized from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and4-bromo-2-fluorobenzyl alcohol according to the methods described inExamples 52 and 54 to give the product as a white solid: δ_(H) (400 MHz,DMSO-d₆) 1.3 (6H, d J, 7.2 Hz), 3.0-3.2 (4H, m), 4.3 (2H, sextet, J 7.2Hz), 5.15 (2H, s), 7.42 (2H, m), 7.6 (1H, m), 9.15 (1H, br) and 9.80(1H, br); LC (XTERRA, 50/80, 220 nm) 89.8% (3.62 min).

Example 56

[0619] Benzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride wasprepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and benzylalcohol according to the methods described for Examples 52 and 54 togive the product as a cream solid (0.0833 g, 15% overall); ν_(max)(nujol)/cm-1 2776, 2672, 2568, 2527, 1706, 1581, 1415, and 1329; δ_(H)(400 MHz, DMSO-d₆) 9.89 (1 H, br), 9.19 (1 H, br), 7.41-7.31(5 H, m),5.13 (2 H, s), 4.34 (2 H, m), 3.17-3.08 (4 H, m), and 1.31 (6 H, d, J7.2).

Example 57

[0620] 2-Chlorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2-chloro-benzyl alcohol according to the methods described for Examples52 and 54 to give the product as a white solid (0.0901 g, 14% overall);ν_(max) (nujol)/cm-1 3375, 2689, 2577, 1699, 1592, 1380, 1328, and 1300;δ_(H) (400 MHz, DMSO-d₆) 9.62 (2 H, br), 7.50 (2 H, m), 7.40 (2 H, m),5.19 (2 H, s), 4.33 (2 H, m), 3.18-3.06 (4 H, m), and 1.31 (6 H, d, J7.2).

Example 58

[0621] (R)-2-Fluorobenzyl 2-methylpiperazine-1-carboxylate hydrochloride

[0622] To a stirred solution of(R)1-tert-butoxycarbonyl-4-chlorocarbonyl-2-methylpiperazine (348 mg,1.32 mmol), triethylamine (550 uL, 3 eq) and 2-fluorobenzyl alcohol (420uL, 2 eq) in dichloromethane (8 mL) were added pyridine (110 uL, 1 eq)and DMAP (cat.). The resultant mixture was stirred at ambienttemperature for 5 days. Purification by flash column chromatography[SiO₂; ethyl acetate—heptane (1:3)] afforded a colourless oil (692 mg).This material was dissolved in MeOH (12 mL) and treated with a solutionof HCl in dioxane (4 M; 3.3 mL, ˜10 equiv.), with overnight stirring.Purification by flash column chromatography [SiO₂; ethylacetate—methanol—ammonium hydroxide (90:8:2)] afforded a colourless oil.Dissolution in dichloromethane (4 mL) and treatment with HCl in dioxane(4 M; 1 mL) afforded, after evaporation the desired product (368 mg,79%) as a white solid: δ_(H)(400 MHz; d₆-DMSO) 1.26 (3H, d, J 7.0 Hz),2.81-2.94 (1H, m), 3.01-3.27 (4H, m), 3.90-3.98 (1H, m), 4.31-4.40 (1H,m), 5.13 (1H, d, J 12.5 Hz), 5.17 (1H, d, J 12.5 Hz), 7.20-7.26 (2H, m),7.38-7.50 (2H, m), 9.13 (1H, br s) and 9.59 (1H, br s); LC (XTERRA,30/70, 210 nm) 99.6% (2.01 min).

Example 59

[0623] 2-Fluoro-4-propylbenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride

[0624] 2-Fluoro-4-propylbenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate:tetrakis(triphenylphosphine)palladium(O) (0.029 g) was added to asolution of 4-bromo-2-fluorobenzyl4-tert-butoxycarbonyl-2,6-dimethylpiperazine-1-carboxylate (from Example55, 0.223 g, 0.5 mmol) and n-propylzinc bromide (0.5 M THF, 3.0 ml) indry THF (5 ml) under Ar. The reaction mixture was heated to reflux for19 h, then cooled to ambient temperature and partitioned between ethylacetate (50 ml) and saturated aqueous ammonium chloride solution (50ml). The organic phase was separated, washed with water and brine, dried(sodium sulfate) and the solvent evaporated under reduced pressure toafford the crude product as an oil, which was purified by silica gelchromatography (DIPE:heptane, 1:1) and used immediately.

[0625] 2-Fluoro-4-propylbenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from 2-fluoro-4-propylbenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate accordingto the method described in Example 52: δ_(H)(400 MHz; d₆-DMSO) 0.9 (3H,t, J 7.3 Hz), 1.3 (6H, d, J 7.2 Hz), 1.59 (2H, sextet, J 7.3 Hz), 2.58(2H, t, J 7.3 Hz), 3.0-3.2 (4H, m), 4.25 (2H, sextet, J 7.2 Hz), 5.15(2H, s), 7.0-7.1 (2H, m), 7.38 (1H, t, J 7.9 Hz) and 9.0-10.0 (2H, br);HPLC (XTERRA, 50/80, 220 nm) 91% (4.93 min).

Example 60

[0626] S-4-[(Ethylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and ethyl isocyanateaccording to the method described in Example 71 to give the product as awhite solid (58.6%); melting point 153.1-157.6° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 1.069 (3H, t, J 7.0 Hz), 3.116 (6H, m), 3.667(4H, bs),4.140(2H, s), 7.020(2H, d, J 8.5 Hz), 7.325(2H, d, J 8.5 Hz), 7.744(1H,t, J 5.5 Hz) and 9.117(2H, bs).

Example 61

[0627] S-4-[[(2-Chloroethyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and2-chloroethyl isocyanate according to the method described in Example 71to give the product as a white solid (73.8%); melting point 206.3-206.4°C.; NMR δ_(H) (400 MHz, DMSO-d₆) 3.120(4H, bt), 3.385 (3H, q, J 6.0 Hz),3.367(6H, m), 4.146(2H, s), 7.040(2H, d, J 9.0 Hz), 7.337(2H, d, J 8.5Hz), 8.045(1H, t, J 5.5 Hz) and 8.987(2H, bs).

Example 62

[0628] S-4-[(Butylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and butyl isocyanateaccording to the method described in Example 71 to give the product as awhite solid (65.7%); melting point 176.7-177.7° C.; NMR δH (400 MHz,DMSO-d₆) 0.884(3H, t, J 7.0 Hz), 1.310(2H, m), 1.436(2H, m), 3.041(2H,q, J 6.0 Hz), 3.105(4H, bt), 3.638(4H, bs), 4.132(2H, s), 7.015(2H, d, J8.5 Hz), 7.323(2H, d, J 9.0 Hz) 7.736(2H, t, J 6.0 Hz) and 8.733(2H,bs).

Example 63

[0629] S-4-[(2-Propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate andpropyl isocyanate according to the method described in Example 71 togive the product as a white solid (83.7%); HPLC (XTERRA, 50/80, 220 nm)87% (1.15 min), NMR δ_(H) (400 MHz, DMSO-d₆) 1.113(6H, d, J 6.5 Hz),3.108(4H, bt), 3.638(5H, bm), 4.138(2H, s), 7.020(2H, d, J 8.5 Hz),7.321(2H, d, J 8.5 Hz), 7.682(1H, bd) and 8.721(2H, bs).

Example 64

[0630] S-4-[(Benzylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and benzyl isocyanateaccording to the method described in Example 71 to give the product as awhite solid (62.1%); HPLC (XTERRA, 50/80, 220 nm) 89% (1.15 min); NMRδ_(H) (400 MHz, DMSO-d₆) 3.113(4H, bs), 3.634(4H, bs), 4.144(2H, s),4.256(2H, s), 7.110(2H, d, J 8.5 Hz), 7.328(7H, m), 8.328(1H, bs) and8.890(2H, bs).

Example 65

[0631] S-4-[[(2-Methylbenzyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and2-methylbenzyl isocyanate according to the method described in Example71 to give the product as a white solid (62.1%); HPLC (XTERRA, 50/80,220 nm) 89% (1.15 min); NMR δ_(H) (400 MHz, DMSO-d₆) 3.113(4H, bs),3.634(4H, bs), 4.144(2H, s), 4.256(2H, s), 7.110(2H, d, J 8.5 Hz),7.328(7H, m), 8.328(1H, bs) and 8.890(2H, bs).

Example 66

[0632] 4-Difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride

[0633] 4-Difluoromethoxybenzyl alcohol: to a stirred solution of4-difluoromethoxybenzaldehyde (1.0 g) in methanol (20 ml) was addedsodium borohydride (0.11 g). The mixture was stirred for 2 h thenconcentrated in vacuo and partitioned between dichloromethane (50 ml)and dilute aqueous sodium hydroxide solution (50 ml). The organic layerwas washed (water, brine), dried (sodium sulfate) and concentrated invacuo to give the product as an oil (0.89 g), which was used withoutfurther purification.

[0634] 4-Difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and4-difluoromethoxybenzyl alcohol according to the methods described forExamples 52 and 54 to give the product as a white solid (0.202 g, 58%overall); (Found: C, 51.4; H, 6.2; N, 8.0%. C₁₅H₂₀F₂N₂O₃.HCl requires C,51.4; H, 6.0; N, 8.0%); δ_(H) (400 MHz, DMSO-d₆) 9.87 (2H, br), 7.44(2H, d, J 8.8 Hz), 7.24 (1H, t, J 74 Hz), 7.19 (2H, d, J 8.8 Hz), 5.11(2H, s), 4.32 (2H, m), 3.14 (2H, d, J 13.2 Hz), 3.06 (2H, dd, J 5.2 and13.2 Hz), and 1.31 (6H, d, J 7.2 Hz).

Example 67

[0635] cis-2,6-Dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester fumarate

[0636] 6-(3-Methylbutoxy)nicotinic acid was prepared from6-chloronicotinic acid (0.50 g), 3-methyl-1-butanol (0.36 ml) and sodiumhydride (60%, 0.32 g) according to the method described in Example 54 togive the product as a white solid (0.25 g, 38%): δ_(H) (400 MHz,DMSO-d₆) 12.97 (1H, m), 8.71 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5Hz), 6.87 (1H, d, J 8.5 Hz), 4.36 (2H, t, J 7 Hz), 1.75 (1H, nonet, J6.5 Hz), 1.62 (2H, 1, J 6.5 Hz) and 0.93 (6H, d, J 6.5 Hz); HPLC(XTERRA, 20/50, 220 nm) 99% (3.90 min).

[0637] [6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol was prepared from6-(3-methylbutoxy)nicotinic acid (0.24 g) and lithium aluminium hydride(0.5M, THF, 3.5 ml) according to the method described in Example 54 togive the product as a yellow oil (0.19 g, 86%): δ_(H) (400 MHz, CDCl₃)8.08 (1H, d, J 2.5 Hz), 7.59 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5Hz), 4.60 (2H, s), 4.30 (2H, t, J 6.5 Hz), 1.81 (1H, nonet, J 6.7 Hz),1.66 (3H, q, J 7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80,235 nm) 86% (2.54 min).

[0638] cis-2,6-Dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester was prepared from[6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol (0.19 g), sodium hydride(60%, 0.048 g) and4-tert-butoxycarbonyl-1-chlorocarbonyl-cis-2,6-dimethylpiperazine (0.25g) according to the method described in Example 54 to give the productas a pale oil (0.052 g, 13%): δ_(H) (400 MHz, CDCl₃) 8.15 (1H, d, J 2.5Hz), 7.58 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5 Hz), 5.07 (2H, s),4.32 (2H, t, J 7 Hz), 4.18 (2H, m), 3.95 (2H, m), 2.95 (2H, m), 1.81(1H, nonet, J 7 Hz), 1.67 (2H, q, J 7 Hz), 1.47 (9H, s), 1.22 (6H, d, J7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80, 235 nm) 91% (7.19min).

[0639] cis-2,6-dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester fumarate was prepared fromcis-2,6-dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester (0.05 g) and HCl (4M,dioxane, 0.2 ml) according to the method described in Example 48 to givethe product as a white solid (0.012 g, 28%): □_(H) (400 MHz, DMSO-d₆)8.15 (1H, d, J 2.5 Hz), 7.69 (1H, dd, J 8.5, 2 Hz), 6.79 (1H, d, J 8.5Hz), 6.60 (2H, s), 5.02 (2H, s), 4.27 (2H, t, J 7 Hz), 3.95 (2H, m),2.75 (2H, d, J 12 Hz), 2.68 (2H, dd, J 12, 4 Hz), 1.74 (1H, nonet, J 6.7Hz), 1.60 (2H, q, J 7 Hz), 1.18 (6H, d, J 7 Hz) and 0.92 (6H, d, J 6.5Hz); HPLC (XTERRA, 50/80, 235 nm) 95% (4.46 min).

Example 68

[0640] cis-2,6-Dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester hemifumarate

[0641] 6-(Cyclohexylmethoxy)nicotinic acid was prepared from6-chloronicotinic acid (0.50 g), cyclohexylmethanol (0.41 ml) and sodiumhydride (60%, 0.32 g) according to the method described in Example 54 togive the product as a white solid (0.42 g, 56%): δ_(H) (400 MHz,DMSO-d₆) 12.97 (1H, br), 8.70 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5,2.5 Hz), 6.88 (1H, d, J 8.5 Hz), 4.14 (2H, d, J 6 Hz), 1.81-1.60 (6H,m), 1.20 (3H, sept of triplets, J 12, 2.5 Hz) and 1.03 (2H, dq, J 11,2.5 Hz); HPLC (XTERRA, 50/80, 220 nm) 100% (1.47 min).

[0642] [5-(2-Cyclohexylmethoxy)pyridyl]methanol was prepared from6-cyclohexylmethoxynicotinic acid (0.39 g) and lithium aluminium hydride(0.5M, THF, 3.5 ml) according to the procedure described for Example 54to give the product as a yellow oil (0.36 g, 96%): δ_(H) (400 MHz,CDCl₃) 8.07 (1H, d, J 2.5 Hz), 7.60 (1H, dd, J 8.5, 2.5 Hz), 6.72 (1H,d, J 8.5 Hz), 4.60 (2H, s), 4.08 (2H, d, J 6.5 Hz), 1.88-1.67 (6H, m),1.24 (3H, septet of triplets, J 12, 3 Hz) and 1.04 (2H, dq, J 12, 3 Hz);HPLC (XTERRA, 50/80, 235 nm) 77% (4.49 min).

[0643] cis-2,6-Dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester was prepared from[5-(2-cyclohexylmethoxy)pyridyl]methanol (0.36 g), sodium hydride (60%,0.77 g) and4-tert-butoxycarbonyl-1-chlorocarbonyl-cis-2,6-dimethylpiperazine (0.40g) according to the method described for Example 54 to give the productas a pale oil (0.035 g, 5%): δ_(H) (400 MHz, CDCl₃) 8.14 (1H, d, J 2.5Hz), 7.58 (1H, dd, J 8.5, 2.5 Hz), 6.72 (1H, d, J 8.5 Hz), 5.07 (2H, s),4.18 (2H, m), 4.09 (2H, d, J 6.5 Hz), 3.92 (2H, m), 2.95 (2H, m),1.88-1.65 (6H, m), 1.47 (9H, s), 1.25 (3H, septet of triplets, J 12.5, 3Hz), 1.22 (6H, d, J 7 Hz) and 1.05 (2H, dq, J 13, 3 Hz); HPLC (XTERRA,50/80, 235 nm) 91% (8.06 min).

[0644] cis-2,6-Dimethyl-piperazine-1-carboxylic acid6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester hemifumarate was preparedfrom [5-(2-cyclohexylmethoxy)pyridyl]methyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate (0.03 g)and HCl (4M, dioxane, 0.2 ml) according to the method described inExample 48 to give the product as a white solid (0.011 g, 45%): δ_(H)(400 MHz, DMSO-d₆) 8.14 (1H, d, J 2.5 Hz), 7.69 (1H, dd, J 8.5, 2.5 Hz),6.80 (1H, d, J 8.5 Hz), 6.58 (1H, s), 5.01 (2H, s), 4.06 (2H, d, J 6Hz), 3.93 (2H, m), 2.73 (2H, d, J 12 Hz), 2.67 (2H, dd, J 12, 4.5 Hz),1.80-1.60 (6H, m), 1.19 (3H, septet of triplets, J 12, 3 Hz), 1.17 (6H,d, J 7 Hz) and 1.02 (2H, m); HPLC (XTERRA, 50/80, 235 nm) 100% (5.83min).

Example 69

[0645] 4-Ethyl-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate

[0646] 4-Ethyl-2-fluorobenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate wasprepared from 4-bromo-2-fluorobenzyl4-tert-butylpiperazine-1-carboxylate and diethylzinc according to themethod described for Example 59.

[0647] 4-Ethyl-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatewas prepared from 4-ethyl-2-fluorobenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate accordingto the methods described for Example 54 to give the product as a yellowoil: δ_(H) (400 MHz, DMSO-d₆) 1.18 (3H, t, J 7.7 Hz), 1.28 (6H, d, J 7.2Hz), 2.62 (2H, q, J 7.7 Hz), 3.05-3.2 (4H, m), 4.28 (2H, sextet, J 7.1Hz), 5.15 (2H, s), 7.05-7.1 (2H, m), 7.39 (1H, t, J 7.9 Hz) and 9.0-10.0(2H, br); HPLC (XTERRA, 50/80, 220 nm) 96% (3.65 min).

Example 70

[0648] 2-Fluoro-4-pentylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate

[0649] 2-Fluoro-4-pentylbenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate wasprepared from 4-bromo-2-fluorobenzyl4-tert-butylpiperazine-1-carboxylate and dipentylzinc according to themethod described for Example 59.

[0650] 2-Fluoro-4-pentylbenzyl cis-2,6-dimethylpiperazine-1-carboxylatewas prepared from 2-fluoro-4-pentylbenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate accordingto the methods described for Example 54 to give the product as a yellowoil: δ_(H) (400 MHz, DMSO-d₆) 0.85 (3H, t, J 7.0 Hz), 1.27 (10H, m),1.55 (2H, sextet, J 7.0 Hz), 2.60 (2H, t, J 7.0 Hz), 3.03-3.2 (4H, m),4.30 (2H, sextet, J 7.1 Hz), 5.15 (2H, s), 7.05-7.1 (2H, m), 7.39 (1H,t, J 7.9 Hz) and 8.8-9.8 (2H, br); HPLC (XTERRA, 50/80, 220 nm) 96%(6.46 min).

Example 71

[0651] S-4-[(tert-Butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride

[0652] S-4-[(tert-Butylamino)carbonyl]oxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate: to a stirred solutionof S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate(1.35 g, 3.7 mmol) in dichloromethane (50 mL) were added tert-butylisocyanate (0.85 ml, 7.4 mmol) and triethylamine (0.1 ml). The mixturewas stirred for 18 h then diluted with isohexane (30 mL) andconcentrated in vacuo. The solid residue was washed with isohexane togive the crude product as a white solid (1.74 g, >100%) which was usedwithout further purification.

[0653] To a stirred solution of the crude product from above (3.7 mmol)in methanol (10 mL) was added dropwise HCl-dioxane (4M, 9.2 ml, 10 eq.).The mixture was stirred at room temperature for 4 h then concentrated invacuo. Diethyl ether (10 mL) was added to the residue which was left tostand for 18 h. The precipitate formed was filtered-off, washed withether and dried to give the title compound as a white, crystalline solid(1.15 g, 80%): HPLC (XTERRA, 50/80, 220 nm) 91.4% (1.81 min); NMR δ_(H)(400 MHz, DMSO-d₆) 1.269(9H, s), 3.119(4H, bt), 3.673(4H, bs), 4.141(2H,s), 6.998(2H, d, J 8.5 Hz), 7.322(2H, d, J 8.5 Hz) and 7.522(1H, s).

Example 72

[0654] 2,5-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2,5-difluorobenzyl alcohol according to the methods described forExamples 52 and 54 to give the product as a white solid (0.247 g, 77%overall); (Found: C, 52.5; H, 6.1; N, 8.7%. C₁₄H₁₈F₂N₂O₂.HCl requires C,52.4; H, 6.0; N, 8.7%); δ_(H) (400 MHz, DMSO-d₆), 9.98 (2H, br),7.29(3H, m), 5.15 (2H, s), 4.31 (2H, m), 3.15 (2H, d, J 12.8 Hz), 3.06 (2H,dd, J 5 and 13 Hz), and 1.31 (6H, d, J 7.2 Hz).

Example 73

[0655] 2,3-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2,3-difluorobenzyl alcohol according to the methods described forExamples 52 and 54 to give the product as a white solid (0.1846 g, 57%overall); (Found: C, 52.4; H, 6.0; N, 8.6%. C₁₄H₁₈F₂N₂O₂.HCl requires C,52.4; H, 6.0; N, 8.7%); δ_(H) (400 MHz, DMSO-d₆) 10.07 (1H, br), 9.33(1H, br), 7.44 (1H, m), 7.28 (2H, m), 5.21 (2H, s), 4.30 (2H, m), 3.14(2H, d, J 13.2 Hz), 3.06 (2H, m), and 1.31(6 H, d, J 7.2 Hz).

Example 74

[0656] 2,6-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride

[0657] 2,6-Difluorobenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate wasprepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2,6-difluorobenzyl alcohol according to the method described for Example54 to give the product as a colourless gum (0.251 g, 65%); Rf (Silica,isopropyl ether) 0.35; δ_(H) (400 MHz, CDCl₃) 7.29 (1H, m), 6.90 (2H,m), 5.23 (2H, s), 4.16 (2H, m), 3.92 (2H, br), 2.95 (2H, br), 1.47 (9H,s), 1.21 (6H, d, J 6.8 Hz).

[0658] 2,6-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from 2,6-difluorobenzyl4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate accordingto the method described for Example 52 to give the title compound as awhite solid (0.1585 g, 76%); (Found: C, 52.5; H, 6.3; N, 8.7%.C₁₄H₁₈F₂N₂O₂.HCl requires C, 52.4; H, 6.0; N, 8.7%); δ_(H) (400 MHz,DMSO-d₆) 10.02 (1H, br, s), 9.29 (1H, br, s), 7.51 (1H, m), 7.16 (2H,m), 5.18 (2H, s), 4.24 (2H, m), 3.12 (2H, d, J 12.8 Hz), 3.04 (2H, dd, J5 and 12.8 Hz), and 1.28 (6H, d, J 7.2 Hz).

Example 75

[0659] 2,4-Dimethylbenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2,4-dimethylbenzyl alcohol according to the methods described forExamples 52 and 54 to give the product as a hygroscopic white solid(0.1384 g, 44% overall); (Found: C, 60.9; H, 8.1; N, 8.9%.C₁₆H₂₄N₂O₂.HCl.0.25H₂O requires C, 60.6; H, 8.1; N, 8.8%); δ_(H) (400MHz, DMSO-d₆) 9.53 (2H, br), 7.19 (1H, d, J 7.6 Hz), 7.03 (1H, s), 6.99(1H, d, J 7.6 Hz), 5.07 (2H, s), 4.29 (2H, m), 3.13 (2H, d, J 13.2 Hz),3.04 (2H, dd, J 5.2 and 13.2 Hz), 2.27 (3H, s), 2.26 (3H, s) and 1.29(6H, d, J 7.2 Hz).

Example 76

[0660] S-4-[(Propylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylatehydroxide was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and propyl isocyanateaccording to the method described in Example 71 to give the product as awhite solid (25.3%); HPLC (XTERRA, 50/80) 98% (1.18 min); NMR δ_(H) (400MHz, DMSO-d₆) 0.877(3H, t, J 7.5 Hz), 1.470(2H, m), 3.006(2H, q, J 6.5Hz), 3.112(4H, bt), 3.673(4H, bt), 4141(2H, s), 7.017(2H, d, J8.5 Hz),7.323(2H, d, J 8.5 Hz), 7.715(1H, t) and 9.126 (2H, bs).

Example 77

[0661] S-4-[(Cyclohexylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate andcyclohexyl isocyanate according to the method described in Example 71 togive the product as a white solid (41.4%); HPLC (XTERRA, 50/80) 89%(3.63 min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.234(6H, m), 1.554(1H, bd),1.700(2H, bd), 1.808(2H, bd), 3.113(4H, bt), 3.677(4H, bs), 4.142(2H,s),7.012(2H, d, J 8.5 Hz), 7.316(2H, d, J 8.0 Hz), 7.661(1H, d) and9.189(1H, bs).

Example 78

[0662] 2-Fluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate

[0663] 2-Fluoro-4-hydroxybenzyl alcohol: to a stirred solution of3-fluorophenol (10.4 g) and potassium hydroxide (85%, 6.1 g) in water(20 ml) at 60° C. was added dropwise over 1 h a solution of 37% aqueousformaldehyde solution (14.3 ml) in added water (20 ml). The mixture wascooled to 40° C., stirred for 18 h then cooled to room temperature andacidified with dilute hydrochloric acid. The mixture was extracted withethyl acetate (2×100 ml). The combined organic extracts were washed(water, brine), dried (sodium sulfate), concentrated in vacuo andpurified by column chromatography (SiO₂; ethyl acetate—isohexane, 1:1)to give the product as a white, crystalline solid (1.0 g, 8%): δ_(H)(400 MHz, DMSO-d₆) 9.70 (1H, m, OH), 7.21 (1H, t, J 8.5 Hz), 6.58 (1H,dd, J 8, 2, Hz), 6.51 (1H, dd, J 12, 2 Hz), 4.98 (1H, m, OH) and 4.41(2H, s); HPLC (XTERRA, 50/80, 235 nm) 93% (0.54 min).

[0664] 4-Difluoromethoxy-2-fluorobenzyl alcohol: to a stirred solutionof powdered potassium hydroxide (85%, 2.2 g) in 2-propanol (20 ml) wasadded dropwise a solution of 2-fluoro-4-hydroxybenzyl alcohol (1.0 g) in2-propanol (5 ml). The mixture was cooled to −10° C. andchlorodifluoromethane was bubbled into the stirred mixture for 10 min.The reaction vessel was sealed and the mixture was stirred for 30 min at−10° C. then warmed slowly to room temperature and stirred for 18 h. Themixture was partitioned between ethyl acetate (2×30 ml) and water (30ml). The combined organic extracts were washed (water, brine), dried(sodium sulfate), concentrated in vacuo and purified by columnchromatography [SiO₂, isohexane-ethyl acetate (9:1→4:1)] to give theproduct as a clear oil (0.47 g, 35%): δ_(H) (400 MHz, CDCl₃) 7.43 (1H,t, J 8 Hz), 6.94 (1H, dd, J 8, 2.5 Hz), 6.87 (1H, dd, J 10.5, 2.5 Hz),6.50 (1H, t, J 73 Hz) and 4.74 (2H, d, J 6 Hz).

[0665] 4-Difluoromethoxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and4-difluoromethoxy-2-fluorobenzyl alcohol according to the methodsdescribed for Example 48 to give the product as an off-white solid(0.072 g, 41% overall); ν_(max) (nujol)/cm−1 3391, 2595, 1702, 1630,1511, 1420, 1378, and 1342; δ_(H) (400 MHz, DMSO-d₆) 7.48 (1H, m), 7.30(1H, t), 7.18-7.14 (2H, m), 6.58 (2H, s), 5.10 (2H, s), 3.97 (2H, t, J 6Hz), 2.79 (2H, d, J 12.5 Hz), 2.72 (2 H, dd, J 4.3 and 12.3 Hz), and1.19 (6 H, d,J6.9 Hz).

Example 79

[0666] 3-Benzyloxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and3-benzyloxybenzyl alcohol according to the methods described forExamples 52 and 54 to give the product as a white solid (0.254 g, 65%overall); ν_(max) (nujol)/cm−1 3320, 2684, 2587, 1716, 1694, 1599, 1415,and 1312; δ_(H) (400 MHz, DMSO-d₆) 10.02 (1H, br), 9.27 (1H, br),7.45-7.28 (6H, m), 7.01-6.94 (3H, m), 5.11 (2H, s), 5.09 (2H, s), 4.33(2H, m), 3.15 (2H, d, J 13.2 Hz), 3.07 (2H, m), and 1.31 (6H, d, J 7.6Hz).

Example 80

[0667] 2,6-Difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride

[0668] 2,6-Difluoro-4-difluoromethoxybenzyl alcohol: to a stirredsolution of powdered potassium hydroxide (85%, 7.2 g) in 2-propanol (60ml) was added dropwise a solution of 2,6-difluoro-4-hydroxybenzylalcohol (3.5 g) in 2-propanol (20 ml). The mixture was cooled to −10° C.and chlorodifluoromethane was bubbled into the stirred mixture for 10min. The reaction vessel was sealed and the mixture was stirred for 30min at −10° C. then warmed slowly to room temperature and stirred for 18h. The mixture was partitioned between ethyl acetate (2×100 ml) andwater (100 ml). The combined organic extracts were washed (water,brine), dried (sodium sulfate), concentrated in vacuo and purified bycolumn chromatography [SiO₂, isohexane-ethyl acetate (9:1→4:1)] to givethe product as a clear oil (1.83 g, 40%): δ_(H) (400 MHz, CDCl₃) 6.74(1H, t, J 4 Hz), 6.70 (1H, t, J 4 Hz), 6.51 (1H, t, J 73 Hz) and 4.75(2H, d, J 6.5 Hz).

[0669] 2,6-Difluoro-4-difluoromethoxybenzylcis-2,6-dimethyl-4-tert-butoxycarbonyl-piperazine-1-carboxylatehydrochloride: to a stirred suspension of sodium hydride (60%, 86 mg,1.5 eq.) in DMF (2 mL) at 0° C. was added dropwise a solution ofcis-2,6-dimethyl-1-(chlorocarbonyl)-4-(tert-butoxycarbonyl)piperazine(0.40 g, 1 eq.) and 4-difluoromethoxy-2,6-difluorobenzyl alcohol (0.30g, 1 eq.) in DMF (5 mL). The mixture was warmed to room temperature,stirred for 2 hours then partitioned between water (20 mL) and ethylacetate (2×20 mL). The combined organic layers were washed (water,brine), dried (sodium sulfate) and concentrated to give a yellow oil(0.72 g), which was used without further purification.

[0670] 2,6-Difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared fromcis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2,6-difluoro-4-difluoromethoxybenzyl alcohol according to the methoddescribed for Example 54 to give the product as a, white solid (0.1406g, 65% overall); ν_(max) (nujol)/cm−1 3342, 1684, 1640, 1599, 1378,1308, 1166, and 1089; δ_(H) (400 MHz, DMSO-d₆) 9.69 (2H, br), 7.38 (1H,t, J 73 Hz), 7.15-7.10 (2H, m), 5.14 (2H, s), 4.24 (2H, m), 3.13 (2H, d,J 13 Hz), 3.05 (2H, dd, J 5.2 and 13 Hz), and 1.27 (6H, d, J 7.2 Hz).

Example 81

[0671] (+/−)-S-4-[(2-Butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride, was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and(+/−)sec-butyl isocyanate according to the method described in Example71 to give the product as a white solid (41.2%); melting point185.7-205.6° C.; NMR δ_(H) (400 MHz, DMSO-d₆) 0.871(3H, t, J 7.5 Hz),1.090(3H, d, J 7.0 Hz), 1.440(2H, m), 3.115(4H, t), 3.455(1H, m),3.672(4H, bt) 4.142(2H, s), 7.012(2H, d, J 8.5 Hz), 7.325(2H, d, J 8.5Hz), 7.584(1H, d) and 9.085(1H, bs).

Example 82

[0672] S-4-[(Cyclopentylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate andcyclopentyl isocyanate according to the method described in Example 71to give the product as a white solid (88.2%); melting point 196.5-197.6°C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.499(4H, m), 1.652(2H, m), 1.828(2H,m), 3.116(4H, bt), 3.312(5H, bs), 3.678(4H, bt), 3.818(1H, m), 4.142(2H,s), 7.017(2H, d, J 8.0 Hz), 7.321(2H, d, J 8.5 Hz), 7.736(1H, d) and9.157(2H, bs).

Example 83

[0673] S-4-[(1-Adamantylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate andadamantanyl isocyanate according to the method described in Example 71to give the product as a white solid (38.2%); melting point 200.7-200.8°C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.612(6H, m), 1.905(6H, m), 2.027(3H,bs), 3.119(4H, bt), 3.669(4H, bs), 4.138(2H, s), 6.987(2H, d, J 8.5 Hz),7.321(2H, d, J 8.5 Hz), 7.449(1H, bs) and 9.070(2H, s).

Example 84

[0674] S-4-[(2-Propenylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate andallyl isocyanate according to the method described in Example 71 to givethe product as a white solid (18.6%); melting point 193.8-193.9° C.; NMRδ_(H) (400 MHz, DMSO-d₆) 3.101(4H, bt), 3.689(4H, bs), 3.757(2H, bs),4.147(2H, s), 5.102(1H, dd, J 1.5, 10.5 Hz), 5.201(1H, d, J 1.5, 17.5Hz), 7.026(2H, d, J 8.5 Hz), 7.332(2H, d, J 8.5 Hz), 7.925(1H, t) and9.431(2H, bs).

Example 85

[0675] S-4-[(Phenylamino)carbonyl]oxybenzyl piperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and cyclohexylisocyanate according to the method described in Example 71 to give theproduct as a white solid (8.0%); melting point 177.9-201.9° C.; NMRδ_(H) (400 MHz, DMSO-d₆) 3.127(4H, bt), 3.687(4H, bs), 4.180(2H, s),7.055(1H, t, J 7.5 Hz), 7.144(2H, d, J 8.5 Hz), 7.323(2H, t, J 8.5 Hz),7.391(2H, d, J 8.5 Hz), 7.495(2H, d, J 7.5 Hz), 9.078(2H, s) and10.191(1H, s).

Example 86

[0676] S-4-[[4-(2-Propyl)phenylamino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and4-(2-propyl)phenyl isocyanate according to the method described inExample 71 to give the product as a white solid (4.8%); melting point234.2-234.3° C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.179(6H, d, J 7.0 Hz),3.121(4H, bt), 3.647(4H, bs), 4.168(2H, s), 7.141(2H, d, J 8.5 Hz),7.183(2H, d, J 8.5 Hz), 7.387(4H, m), (9.019(2H, bs) and 10.089(1H, s).

Example 87

[0677] (+/−)-S-4-[[(1-Phenylethyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and1-phenylethyl isocyanate according to the method described in Example 71to give the product as a white solid (54.2%); melting point 231.9-232.0°C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.411(3H, d, J 7.0 Hz), 3.101(4H, bt),3.668(4H, bs) 4.132(2H, s), 4.701(1H, m), 7.00(2H, d, J 8.0 Hz),7.327(6H, m), 8.297(1H, bd) and 9.175(2H, bs).

Example 88

[0678]S-4-[[(4-Ethoxycarbonyl)phenylamino]carbonyl]oxybenzylpiperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and4-(ethoxycarbonyl)phenyl isocyanate according to the method described inExample 71 to give the product as a white solid (77.3%); melting point201.0-201.5□C; NMR δH (400 MHz, DMSO-d₆) 1.308(3H, t, J 7.0 Hz),3.122(4H, bt), 3.680(4H, bt), 4.175(2H, s), 4.277(2H, q, J 7.0 Hz),7.183(2H, d, J 8.5 Hz), 7.396(2H, d, J 8.5 Hz), 7.626(2H, d, J 9.0 Hz),7.923(2H, d, J 9.0 Hz), 9.085(2H, bs) and 10.619(1H, bs).

Example 89

[0679] S-4-[[(3-Chloro-4-fluorophenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and3-chloro-4-fluorophenyl isocyanate according to the method described inExample 71 to give the product as a white solid (39.5%); melting point204.1-204.2□C; NMR δ_(H) (400 MHz, DMSO-d₆) 3.113(4H, bt), 3.686(4H,bs), 4.168(2H, s), 7.401(2H, d, J 8.5 Hz), 7.593(4H, m), 7.718(1H, dd, J2.5, 7.0 Hz), 9.229(2H, bs) and 10.458(1H, bs).

Example 90

[0680]S-4-[[(4-Difluoromethoxyphenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and4-difluoromethoxyphenyl isocyanate according to the method described inExample 71 to give the product as a white solid (30.7%); melting point203.7-203.8□C; NMR δ_(H) (400 MHz, DMSO-d₆) 3.116(4H, bt), 3.683(4H,bs), 4.171(2H, s), 7.155(4H, d, J 8.5 Hz), 7.387(2H, d, J 8.5 Hz),7.520(2H, d, J 9.0 Hz), 9.206(2H, s) and 10.285(1H, bs).

Example 91

[0681] 4-Methylbenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and4-methylbenzyl alcohol according to the methods described for Examples52 and 54 to give the product as a white solid (0.2614 g, 87% overall);λ_(max) (diffuse reflectance)/cm−1 2749, 2656, 2541, 1697, 1594, 1518,1330, and 1112; δ_(H) (400 MHz, DMSO-d₆) 10.05 (1H, br), 9.32 (1H, br),7.26 (2H, d, J 8.0 Hz), 7.18 (2H, d, J 8.0 Hz), 5.07 (2H, s), 4.30 (2H,m), 3.14 (2H, d, J 12.8 Hz), 3.05 (2H, m), 2.30 (3H, s), and 1.30 (6H,d, J 7.2 Hz).

Example 92

[0682] (+/−)-4-Difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylatefumarate

[0683] (RS) 4-Tert-butoxycarbonyl-2-ethylpiperazine: to a stirredsolution of 2-ethylpiperazine dihydrochloride (J.Org.Chem., 1987, 52(6),1045, 5.0 g) and triethylamine (9.3 ml) in DCM (50 ml) at 0° C. wasadded di-tert-butyl-dicarbonate (6.5 g). The mixture was warmed to roomtemperature, stirred for 2 h, washed successively with water, dilutesodium hydroxide solution, water and brine then dried (sodium sulfate)and concentrated in vacuo to give the product as a clear oil (5.1 g);δ_(H) (400 MHz, CDCl₃) 3.78 (1H, m), 3.71 (1H, d, J 12.5 Hz), 2.81 (1H,dt, J 11.5, 2.5 Hz), 2.69 (1H, t, J 10.5 Hz), 2.48 (1H, td, J 11.5, 3Hz), 2.29 (1H, m), 2.17 (1H, m), 1.39 (9H, s), 1.31 (1H, dd, J 7.5, 6Hz), 1.25 (1H, dd, J 7.5, 6 Hz) and 0.87 (3H, t, J 7 Hz); GC (150° C.−10 min-32° C.) 93%, 5.13 min.

[0684] (RS) 1-Chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine: asolution of (RS)4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g) andpyridine (1.64 ml) in DCM (35 ml) was added dropwise to a stirredsolution of triphosgene (2.1 g) in DCM (100 ml) at 0° C. under Ar. Themixture was warmed to room temperature, stirred for 30 min then washedwith water (100 ml) and brine (100 ml). The organic solution was dried(sodium sulfate) and concentrated in vacuo. The residue was dissolved inisohexane, filtered and concentrated in vacuo to give the product as aclear oil (3.73 g) which was used without further purification; δ_(H)(400 MHz, CDCl₃) 4.39-3.80 (4H, m), 3.39-2.69 (3H, m), 1.66 (2H, m),1.47 (9H, s), 0.96 (2.7H, d, J 7 Hz) and 0.89 (0.3H, d, J 7 Hz); GC(150° C. −10 min-320° C.) 83%, 8.72 min.

[0685](+/−)4-Difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate:sodium borohydride (0.11 g) was added to stirred4-difluoromethoxybenzaldehyde (1.0 g) in methanol (20 ml). The mixturewas stirred for 2 h then concentrated in vacuo. The residue waspartitioned between DCM (30 ml) and aqueous sodium hydroxide solution(2M, 30 ml). The organic layer was filtered through a PTFE membrane andconcentrated in vacuo to give a clear oil (0.89 g). The residue wascombined with (RS)1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine (1.1 g) andsodium hydride (0.31 g) according to the method described for Example 54to give the product as a yellow oil (1.46 g), which was used withoutfurther purification.

[0686] (+/−)-4-Difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylatefumarate:(+/−)4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate(0.045 g) and HCl-dioxane (4M, 0.2 ml) were combined according to themethod described for Example 48 to give the product as a white solid(0.023 g); δ_(H) (400 MHz, DMSO-d₆) 7.41 (1H, d, J 8 Hz), 7.21 (1H, t, J74 Hz), 7.17 (1H, d, J 8.5 Hz), 6.56 (2H, s), 5.08 (1H, d, J 13 Hz),5.04 (1H, d, J 13 Hz), 3.91 (lH, m), 3.78 (1H, m), 2.90 (3H, m), 2.73(1H, m), 2.57 (1H, m), 1.70 (1H, m), 1.62 (1H, m) and 0.77 (3H, t, J 7Hz).

Example 93

[0687] S-4-[[(4-Methoxyphenyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and4-methoxyphenyl isocyanate according to the method described in Example71 to give the product as a white solid (22.4%); NMR δ_(H) (400 MHz,DMSO-d₆) 2.272(3H, s), 3.354(4H, bm), 3.445(4H, bs), 4.162(2H, s),6.860(1H, d, J 7.5 Hz), 7.139(2H, d, J 9.0 Hz), 7.192(1H, t, J 7.5 Hz),7.293(2H, d, J 8.5 Hz), 7.370(2H, d, J 8.5 Hz) and 10.104(1H, bs).

Example 94

[0688] S-4-[ [(3-Methylbenzyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and3-methylbenzyl isocyanate according to the method described in Example71 to give the product as a white solid (58.4%); NMR δ_(H) (400 MHz,DMSO-d₆) 2.302(3H, s), 3.344(4H, bm), 3.436(4H, bs), 4.125(2H, s),4.231(2H, d, J 6.5 Hz), 7.071(5H, m), 7.228(1H, t, J 7.5 Hz), 7.318(2H,d, J 8.5 Hz) and 8.232(1H, t, J 6.5 Hz).

Example 95

[0689] S-4-[[(4-Methoxybenzyl)amino]carbonyl]oxybenzylpiperazine-1-thiocarboxylate hydrochloride was prepared fromS-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and4-difluoromethoxyphenyl isocyanate according to the method described inExample 71 to give the product as a white solid (66.0%); δ_(H) (400 MHz,DMSO-d₆) 3.338(4H, bm), 3.437(4H, bs), 3.737(3H, s), 4.116(2H, s),4.184(2H, d, J 6.0 Hz), 6.902(2H, d, J 8.5 Hz), 7.024(2H, d, J 8.5 Hz),7.227(2H, d, J 9.0 Hz), 7.318(2H, d, J 8.5 Hz) and 8.193(1H, t, J 6.0Hz).

Example 96

[0690] 2,6-Difluoro-4-(2-propyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate

[0691] 2,6-Difluoro-4-(2-propoxy)benzyl alcohol: a mixture of2,6-difluoro-4-hydroxybenzyl alcohol (0.20 g), cesium carbonate (0.22 g)and 2-iodopropane (0.14 ml) in DMF (10 ml) was heated to 40° C. andstirred for 18 h. The mixture was cooled to room temperature then pouredinto water (30 ml) and extracted with ethyl acetate (2×20 ml). Thecombined organic extracts were washed (water, brine), dried (sodiumsulfate) and concentrated in vacuo to give the product as a yellow oil(0.25 g) which was used without further purification: δ_(H) (400 MHz,CDCl₃) 6.44 (1H, t, J 4 Hz), 6.40 (1H, t, J 4 Hz), 4.69 (2H, d, J 5.5Hz), 4.48 (1H, hept., J 6 Hz) and 1.33 (6H, d, J 6 Hz).

[0692] 2,6-Difluoro-4-(2-propoxy)benzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2,6-difluoro-4-(2-propoxy)benzyl alcohol according to the methodsdescribed for Examples 48 and 54 to give the product as a white solid:δ_(H) (400 MHz, DMSO-d₆) 1.16 (6H, d, J 6.9 Hz), 1.26 (6H, d, J 6.0 Hz),2.65-2.8 (4H, m), 3.90 (2H, m), 4.68 (1H, heptet, J 6.0 Hz), 5.02 (2H,s), 6.6 (2H, s, fumarate) and 6.75 (2H, m), NH not observed; HPLC(XTERRA, 50/80, 220 nm) 94% (4.00 min).

Example 97

[0693] S-4-(2-Oxo-2-phenylethoxy)benzyl piperazine-1-thiocarboxylate

[0694] 4-(2-Oxo-2-phenylethoxy)benzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate: a mixture of4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (100mg, 0.28 mmol), cesium carbonate (140 mg, 1.5 eq) anda-bromoacetophenone (84 mg, 1.5 eq) in DMF was shaken at ambienttemperature for 16 h. The reaction mixture was poured into water (30 mL)and extracted with ethyl acetate (3×20 mL). The organic extracts werewashed with water (30 mL), dried (MgSO₄) and condensed to give thedesired product (129 mg, 96%) as a yellow oil: NMR δ_(H)(400 MHz;d₆-DMSO) 1.40 (9H, s), 3.30-3.36 (4H, m), 3.43 (4H, br s), 4.07 (2H, s),5.54 (2H, s), 6.86-6.91 (2H, m), 7.20-7.26 (2H, m), 7.54-7.60 (2H, m)and 7.66-7.72 (1H, m); HPLC (XTERRA, 50/80, 220 nm) 96.1% (6.56 min).

[0695] 4-(2-Oxo-2-phenylethoxy)benzyl piperazine-1-thiocarboxylate: asolution of HCl in dioxane (4 M; 380 uL, 10 eq) was added to a solutionof 4-(2-oxo-2-phenylethoxy)benzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (72.1 mg) in ethylacetate (2 mL) and the resultant mixture was shaken at ambienttemperature for 16 h. The solvent was removed in vacuo and the resultantcrude material was suspended in dichloromethane (4 mL) and shaken withMP-CO₃ (1 g, 17 eq) at ambient temperature for 1 h. Purification byion-exchange chromatography [SCX-2 (500 mg); DCM, MeOH, NH₃-MeOH]afforded the desired product (44.7 mg, 79%) as a colourless oil: NMRδ_(H)(400 MHz; CDCl₃) 2.82-2.86 (4H, m), 3.41-3.63 (4H, br s), 4.12 (2H,s), 5.23 (2H, s), 6.84-6.90 (2H, m), 7.24-7.29 (2H, m), 7.46-7.52 (2H,m) and 7.58-7.64 (1H, m); HPLC (XTERRA, 50/80, 235 nm) 97.7% (2.05 min).

Example 98

[0696] (R)-4-Difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylatefumarate

[0697](R)4-Difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate:a sample of crude(+/−)4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate(Example 92, 0.1 g) in solution in isohexane—2-propanol (9:1, 0.7 ml)was separated by HPLC [Chiralcel AD; isohexane—2-propanol (9:1)] to givethe product as a clear oil (0.053 g); δ_(H) (400 MHz, CDCl₃) 7.35 (2H,d, J8.5 Hz), 7.11 (1H, d, J8.5 Hz), 6.51 (1H, t, J74 Hz), 5.13 (1H, d, J12.5 Hz), 5.09 (1H, d, J 12.5 Hz), 4.19-3.82 (4H, m), 3.09-2.70 (3H, m),1.57 (2H, m), 1.46 (9H, m) and 0.88 (3H, m); HPLC [Chiralcel AD 300×4.6mm; hexane—2-propanol (9:1), 1.0 ml/min, 220 nm] 98% (10.51 min).

[0698] (R)4-Difluoromethoxybenzyl-2-ethylpiperazine-1-carboxylatefumarate:(R)4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate(0.045 g) was prepared from(R)4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylateaccording to the method described in Example 48 to give the product as awhite solid (0.023 g); m.p. 164° C. (decomp.); δ_(H) (400 MHz, DMSO-d₆)7.41 (1H, d, J 8 Hz), 7.21 (1H, t, J 74 Hz), 7.17 (1H, d, J 8.5 Hz),6.56 (2H, s), 5.08 (1H, d, J 13 Hz), 5.04 (1H, d, J 13 Hz), 3.91 (1H,m), 3.78 (1H, m), 2.90 (3H, m), 2.73 (1H, m), 2.57 (1H, m), 1.70 (1H,m), 1.62 (1H, m) and 0.77 (3H, t, J 7 Hz).

Example 99

[0699] S-4-Benzenesulfonyloxybenzyl piperazine-1-thiocarboxylatehydrochloride

[0700] 4-Benzenesulfonyloxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate:

[0701] triethylamine (57 uL, 0.41 mmol) and benzenesulfonyl chloride (38uL) was added to a stirred solution of 4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (0.10 g) indichloromethane (3 mL) at ice-bath temperature. The reaction mixture waswarmed to room temperature and stirred for 4 hours. The mixture wasdiluted with water (25 mL) and extracted with dichloromethane (2×30 mL).The combined organics were dried (MgSO₄), filtered and concentratedunder vacuum to reveal a brown gum. Trituration with isohexane affordedthe product as a white solid (44 mg, 32%) which was used without furtherpurification.

[0702] 4-Benzenesulfonyloxybenzyl piperazine-1-thiocarboxylatehydrochloride: to a stirred solution of 4-benzenesulfonyloxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (44 mg) in ethylacetate (2 mL) was added hydrogen chloride solution (4M, dioxane, 0.23mL). The mixture was stirred for 18 h then concentrated under vacuum togive the product as a white crystalline solid (31 mg, 78%): HPLC(XTERRA, 50/80, 220 nm) 98.4% (2.54 min); NMR δ_(H) (400 MHz, DMSO-d₆)3.100(4H, bt), 3.672(4H, bt), 4.123(2H, s), 6.976(2H, d, J 8.5 Hz),7.341(2H, d, J 9.0 Hz), 7.680(2H, t, J 8.0 Hz), 7.826(1H, t, J 7.5 Hz),7.870(2H, d, J 7.0 Hz) and 9.258(2H, bs).

Example 100

[0703] (+/−)-2,6-Difluoro-4-propoxybenzyl2-ethylpiperazine-1-carboxylate fumarate was prepared from(+/−)1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine,1-iodopropane and 2,6-difluoro-4-hydroxybenzyl alcohol according to themethods described for Examples 54 and 96 to give the product as a whitesolid (0.13 g, 42%); m.p. 145-165° C. (decomp.); δ_(H) (400 MHz,DMSO-d₆) 6.77 (1H, t, J 3.5 Hz), 6.73 (1H, t, J, 3.5 Hz), 5.07 (1H, d, J12 Hz), 5.01 (1H, d, J 12 Hz), 3.97 (2H, t, J 6.5 Hz), 3.85 (1H, m),3.72 (1H, m), 2.95-2.85 (3H, m), 2.74 (1H, dd, J 13, 4.5 Hz), 2.57 (1H,td, J 12.5, 3 Hz), 1.71 (2H, sept., J 7 Hz), 1.70 (1H, m), 1.57 (1H,sept. J 6.5 Hz), 0.96 (3H, t, J 7 Hz) and 0.73 (3H, t, J 6.5 Hz).

Example 101

[0704] (+/−)-2,6-Difluoro-4-difluoromethoxybenzyl2-ethylpiperazine-1-carboxylate fumarate was prepared from(+/−)1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine and2,6-difluoro-4-difluoromethoxybenzyl alcohol according to the methodsdescribed for Examples 54 to give the product as a white solid (0.084 g,38%); m.p. 145° C. (decomp.); Found: C, 49.04; H, 4.78; N, 5.87%.C₁₉H₂₂F₄N₂O₇ requires: C, 48.93; H, 4.75; N, 6.00%.

Example 102

[0705] 2-Fluoro-5-methoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride

[0706] 2-Fluoro-5-methoxybenzyl alcohol: sodium borohydride (0.061 g)was added to stirred 2-fluoro-5-methoxybenzaldehyde (0.5 g) in methanol(10 ml). The mixture was stirred for 2 h then concentrated in vacuo. Theresidue was partitioned between DCM (2×15 ml) and aqueous sodiumhydroxide solution (2M, 10 ml). The combined organic layers were washed(water, brine), dried (sodium sulfate) and concentrated in vacuo to givea clear oil (0.5 g), which was used without further purification.

[0707] 2-Fluoro-5-methoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and2-fluoro-5-methoxybenzyl alcohol according to the methods described forExamples 54 to give the product as white crystals (0.2714 g, 82%overall); (Found: C, 53.95; H, 6.7; N, 8.3%. C₁₅H₂₁FN₂O₃.HCl requires C,54.1; H, 6.7; N, 8.4%); δ_(H) (400 MHz, DMSO-d₆) 9.84 (2H, br), 7.16(1H, t, J 9.2 Hz), 6.99 (1H, m), 6.94 (1H, m), 5.13 (2H, s), 4.31 (2H,m, J 6 Hz), 3.73 (3H, s), 3.14 (2H, d, J 13 Hz), 3.06 (2H, dd, J 5.2 and13 Hz), and 1.31 (6H, d, J 7.2 Hz).

Example 103

[0708] 3-Difluoromethoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatefumarate was prepared from cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and3-difluoromethoxybenzyl alcohol according to the methods described forExamples 48 and 54 to give the product as a white solid (0.2816 g, 65%overall); (Found: C, 53.0; H, 5.8; N, 6.4%. C₁₅H₂₀F₂N₂O₃.C₄H₄O₄ requiresC, 53.0; H, 5.6; N, 6.5%); δ_(H) (400 MHz, DMSO-d₆) 7.43 (1H, t, J 8.0Hz), 7.24 (1H, s), 7.21 (1H, t, J 74 Hz), 7.13(2H, m, J 8.0 Hz), 6.59(2H, s), 5.11 (2H, s), 4.02 (2H, m, J 6 Hz), 2.82-2.72 (4 H, m), and1.22 (6H, d, J 6.8 Hz).

Example 104

[0709] S-4-Propanesulfonyloxybenzyl piperazine-1-thiocarboxylatehydrochloride was prepared from S-4-hydroxybenzyl4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and 1-propylsulfonylchloride according to the method described in Examples 71 and 99 to givethe product as a colourless gum (51.6%); HPLC (XTERRA, 50/80, 220 nm)96.3% (1.11 min); δ_(H) (400 MHz, DMSO-d₆) 1.033(3H, t, J 7.5 Hz),1.846(2H, m), 3.117(4H, bs), 3.480(2H, t, J 7.5 Hz), 3.685(4H, bs),4.179(2H, s), 7.269(2H, d, J 9.0 Hz), 7.438(2H, d, J 8.5 Hz) and9.236(2H, bs).

Example 105

[0710] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(pyridin-3-ylmethoxy)-benzyl ester fumarate was preparedfrom 2,6-difluoro-4-hydroxybenzyl alcohol, 3-picolyl chloridehydrochloride and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 54 and 96 to give the product as awhite solid: δ_(H) (400 MHz, DMSO-d₆) 1.25 (6H, d, J 6.9 Hz), 2.78-2.90(4H, m), 4.04 (2H, m), 5.05 (2H, s), 5.10 (2H, s), 6.55 (2H, m), 7.341H, dd, J 0.8, 4.8 Hz), 7.75 (1H, m), 8.62 (1H, dd, J 1.6, 4.8 Hz) and8.67 (1H, m), NH not observed; HPLC (XTERRA, 50/80, 220 nm) 99.6% (1.82min).

Example 106

[0711] (R)-2,6-Difluoro-4-propoxybenzyl 2-methylpiperazine-1-carboxylatefumarate was prepared from(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine,1-iodopropane and 2,6-difluoro-4-hydroxybenzyl alcohol according to themethods described for Examples 54 and 96 to give the product as a whitesolid (19.2%); melting point 193.9-194.0° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 0.958(3H, t, J 7.5 Hz), 1.140(3H, d, J 7.0 Hz), 1.715(2H, m),2.817(2H, m), 2.982(2H, m), 3.687(2H, m), 4.097(1H, bs), 5.027(2H, q, J11.0 Hz), 6.573(2H, s) and 6.773(2H, d, J 10.0 Hz).

Example 107

[0712] (R)-4-Difluoromethoxybenzyl 2-methylpiperazine-1-carboxylatefumarate was prepared from(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine and4-difluoromethoxybenzyl alcohol according to the methods described forExamples 48 and 54 to give the product as a white solid (24.0%); meltingpoint 123.9-124.520 C.; NMR δ_(H) (400 MHz, DMSO-d₆) 1.174(3H, d, J 7.0Hz), 2.622(1H, m), 3.003(2H, m), 3.766(1H, dd, J 2.5, 13 Hz), 4.187(1H,m), 5.067(2H, m), 6.542 (2H, s), 7.178(2H, d, J 9.0 Hz), 7.244(1H, t, J74.0) and 7.424(2H, d, J 8.5 Hz).

Example 108

[0713] 5-Benzyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared fromcis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine,benzyl chloride and 2-fluoro-5-hydroxybenzyl alcohol according to themethods described for Examples 52, 54 and 96 to give the product as awhite solid (0.229 g, 56% overall);(Found; C, 61.5; H, 6.5; N, 6.8%.C₂₁H₂₅FN₂O₃.HCl requires C, 61.7; H, 6.4; N, 6.85%); δ_(H) (400 MHz,DMSO-d₆) 9.86 (1H, br), 9.17 (1H, br), 7.45-7.33 (5H, m), 7.17 (1H, t, J9 Hz), 7.08 (1H, m, J 2.8 Hz), 7.02 (1H, m), 5.12 (2H, s), 5.09 (2H, s),4.29 (2H, m), 3.15 (2H, d, J 12.8 Hz), 3.06 (2H, dd, J 4.8 and 12.8 Hz),and 1.29 (6H, d, J 7.2 Hz).

Example 109

[0714] 2,6-Difluoro-4-(3-phenyl)propoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 3-phenylpropyl bromide and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 48, 54 and 96 to give the productas a white solid: δ_(H) (400 MHz, DMSO-d₆) 1.25 (6H, d, J 6.9 Hz), 2.00(2H, m), 2.64-2.80 (6H, m), 3.88, (2H, m), 4.02 (2H, t, J 6.4 Hz), 5.03(2H, s), 6.60 (2H, s, fumarate), 6.76 (2H, m) and 7.18-7.30 (5H, m), NHnot observed; HPLC (XTERRA, 50/80, 220 nm) 99% (6.75 min).

Example 110

[0715] 4-Bromo-2-fluorobenzyl piperazine-1-carboxylate hydrochloride wasprepared from 4-bromo-2-fluorobenzyl alcohol and1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to themethods described for Examples 52 and 54 to give the product as a whitesolid (26.5%); melting point 209.5-209.6° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 3.078(4H, bt), 3.594(4H, bt), 5.118(2H, s), 7.455(2H, m),7.592(1H, m) and 9.147(2H, bs).

Example 111

[0716] 2,6-Difluoro-4-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, allyl bromide and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 54 and 96: NMR δ_(H) (400 MHz,DMSO-d₆) 1.25 (6H, d, J 6.9 Hz), 2.75-2.87 (4H, m), 4.04 (2H, m), 4.51(2H, dt, J 5.3, 1.5 Hz), 5.14 (2H, s), 5.32 (1H, dq, J 10.5, 1.5 Hz),5.41 (1H, dq, J 17.3, 1.5 Hz), 6.00 (1H, ddt, J 17.3, 10.5, 5.3 Hz) and6.45 (2H, m), NH not observed; HPLC (XTERRA, 50/80, 220 nm) 97.3% (3.89min).

Example 112

[0717] (R)-2,6-Difluoro-4-difluoromethoxybenzyl2-methylpiperazine-1-carboxylate fumarate was prepared from2,6-difluoro-4-difluoromethoxybenzyl alcohol and(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 54 to give the product as a whitesolid (2.9%); HPLC (XTERRA, 50/80, 220 nm) 86.0% (1.55 min); NMR δ_(H)(400 MHz, DMSO-d₆) 1.154(3H, d, J 7.0 Hz), 2.639(1H, bm), 2.863(2H, bm),3.007(2H, bm), 3.714(1H, bd), 4.122(1H, bs), 5.106(2H, q), 6.590(2H, s),7.108(2H, d, J 8.5 Hz) and 7.360(1H, t, J 73 Hz).

Example 113

[0718] 2-Fluoro-5-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride

[0719] 2-Fluoro-5-difluoromethoxybenzyl alcohol: to a stirred solutionof powdered potassium hydroxide (85%, 6.56 g) in 2-propanol (70 ml) wasadded dropwise a solution of 2-fluoro-5-hydroxybenzyl alcohol (1.43 g)in 2-propanol (5 ml). The mixture was cooled to −10° C. andchlorodifluoromethane was bubbled into the stirred mixture for 10 min.The reaction vessel was sealed and the mixture was stirred for 30 min at−10° C. then warmed slowly to room temperature and stirred for 18 h. Themixture was partitioned between isopropyl ether (2×100 ml) and water(350 ml). The combined organic extracts were washed (water, brine),dried (sodium sulfate), concentrated in vacuo and purified by columnchromatography [SiO₂, isopropyl ether-pentane (1:4→1:0)] to give theproduct as a clear oil (0.86 g, 44%): δ_(H) (400 MHz, CDCl₃) 7.25 (1H,m), 7.03 (2H, m), 6.46 (1H, t, J 74 Hz), 4.76 (2H, d, J 6 Hz) and 1.85(1H, t, J 6 Hz).

[0720] 2-Fluoro-5-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from2-fluoro-5-difluoromethoxybenzyl alcohol and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 52 and 54 to give the product as awhite solid (0.1473 g, 84%); ν_(max) (diffuse reflectance)/cm⁻¹ 2780,2314, 1697, 1593, 1501, 1327, 1209, and 1101; δ_(H) (400 MHz, DMSO-d₆)9.74 (1H, br), 9.18 (1H, br), 7.35-7.22 (3H, m), 7.20 (1H, t, J 74 Hz),5.17 (2H, s), 4.31 (2H, m, J 6.4 Hz), 3.16 (2H, d, J 13 Hz), 3.08 (2H,dd, J 5.2 and 13 Hz), and 1.30 (6H, d, J 7.2 Hz).

Example 114

[0721] 5-Ethoxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatefumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, ethyliodide and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 54 and 96 to give the product as awhite solid (23.4%); melting point 142.9-143.3° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 1.046(3H, d, J 6.0 Hz), 1.98(6H, d, J 7.0 Hz), 1.306(3H, t, J7.0 Hz), 2.745(4H, m), 3.985(4H, m), 5.080(2H, s), 6.584(2H, s),6.917(2H, m) and 7.129(1H, t, J 9.0 Hz).

Example 115

[0722] 2-Fluoro-5-propoxybenzyl piperazine-1-carboxylate fumarate wasprepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodopropane and1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to themethods described for Examples 54 and 96 to give the product as a whitesolid (28.9%); melting point 155.9-156.1° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 0.966(3H, t, J 7.5 Hz), 1.711(2H, m), 2.793(4H, bt), 3.397(4H,bt), 3.897(2H, t, J 6.5 Hz), 5.077(2H, s), 6.549(2H, s), 6.937(2H, m)and 7.129(1H, t, J 9.0 Hz).

Example 116

[0723] (R)-2-Fluoro-5-propoxybenzyl 2-methylpiperazine-1-carboxylatefumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol,1-iodopropane and(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 54 and 96 to give the product as awhite solid (26.4%); melting point 162.6-162.7° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 0.963(3H, t, J 7.5 Hz), 1.173(3H, d, J 7.0 Hz), 1.709(2H, m),2.582(1H, m), 2.801(2H, bs), 2.991(2H, bm), 3.731(1H, bdd), 3.895(2H, t,J 6.5 Hz), 4.142(1H, bm), 5.077(2H,q), 6.556(2H, s), 6.931(2H, m) and7.126(1H, t, J 9.0 Hz).

Example 117

[0724] 2-Fluoro-5-propoxybenzyl cis-2,6-dimethylpiperazine-1-carboxylatefumarate diethyl etherate was prepared from 2-fluoro-5-hydroxybenzylalcohol, 1-iodopropane and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 96 to give theproduct as a white solid (14.4%); melting point 142.6-144.1° C.; NMRδ_(H) (400 MHz, DMSO-d₆) 0.958(3H, t, J 7.0 Hz), 1.039(2H, d, J 6.0 Hz),1.199(6H, d, J 7.0 Hz), 1.707(2H, m), 2.756(4H, bm), 3.891(2H, t, J 6.5Hz), 3.978(2H, bm), 5.083(2H, s), 6.571(2H, s), 6.932(2H, m) and7.126(1H, t, J 9.0 Hz).

Example 118

[0725] 5-Butoxy-2-fluorobenzyl piperazine-1-carboxylate fumarate wasprepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodobutane and1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to themethods described for Examples 54 and 96 to give the product as a whitesolid (15.2%); melting point 142.4-143.5° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 0.927(3H, t, J 7.5 Hz), 1.423(2H, m, J 7.5 Hz), 1.679(2H, m, J8.0 Hz), 2.798(4H, bt), 3.402(4H, bt), 3.939(3H, t, J 6.5 Hz), 6.537(2H,s), 6.928(2H, m) and 7.125(1H, t, J 9.0 Hz).

Example 119

[0726] (R)-5-Butoxy-2-fluorobenzyl 2-methylpiperazine-1-carboxylatefumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol,1-iodobutane and(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 54 and 96 to give the product as awhite solid (18%); melting point 171.6-171.7° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 0.928(3H, t, J 7.0 Hz), 1.167(3H, d, J 7.0 Hz), 1.421(2H, m, J7.5 Hz), 1.676(2H, m, J 7.5 Hz), 2.564(2H, bm), 2.787(2H, bs), 2.982(2H,bm), 3.717(1H, bdd), 3.931(2H, t, J 6.5 Hz), 4.122(1H, bm), 5.078(2H,q), 6.566(2H, s), 6.929(2H, m) and 7.123(1H, t, J 9.0 Hz).

Example 120

[0727] 5-Butoxy-2-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatefumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol,1-iodobutane and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 96 to give theproduct as a white solid (24.4%); melting point 153.2-153.5° C.; NMRδ_(H) (400 MHz, DMSO-d₆) 0.923(3H, t, J7.5 Hz), 1.199(6H, d, J 7.0 Hz),1.418(2H, m, J 7.5 Hz), 1.675(2H, m, J 7.5 Hz), 2.761(4H, bm), 3.960(4H,bm), 5.084(2H, s), 6.586(2H, s), 6.935(2H, m) and 7.125(1H, t, J 9.5Hz).

Example 121

[0728] cis-2,6-Dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl esterfumarate

[0729][4-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-phenyl]-methanol:PS-BEMP (1.5 g, 2 eq) was added to a solution of2,6-difluoro-4-hydroxybenzyl alcohol (400 mg, 1.5 eq) in acetonitrile (4mL) and the mixture was shaken for 5 min.4-(Chloromethyl)-3,5-dimethylisoxazole (210 uL, 1.67 mmol) was added andthe resultant mixture was shaken at ambient temperature for 16 h. Themixture was filtered, the resin washed with dichloromethane (4×4 mL) andevaporated to afford the desired product (380 mg, 85%) as a white solid:NMR δ_(H)(400 MHz; d₆-DMSO) 2.20 (3H, s), 2.40 (3H, s), 4.42 (2H, d, J5.5 Hz), 5.95 (2H, s), 5.08 (1H, t, J 5.5 Hz) and 6.76-6.83 (2H, m);HPLC (XTERRA, 50/80, 220 nm) 94.5% (1.03 min).

[0730] cis-2,6-Dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester: asolution of4-tert-butoxycarbonyl-1-chlorocarbonyl-2,6-dimethylpiperazine (307 mg, 1eq) and 4-[4-(3,5-dimethylisoxazolyl)]methoxybenzyl alcohol (300 mg,1.11 mmol) in DMF (3 mL) was added to a suspension of sodium hydride(60%; 67 mg, 1.5 eq) in DMF (2 mL) pre-cooled in dry-ice for 2 min. Thevented mixture was left shaking at ambient temperature for 16 h. Thereaction mixture was poured onto ice-water (15 mL) and the resultantsolid was filtered and washed with water (2×10 mL). Drying in a vacuumoven afforded the desired product (489 mg, 87%) as a low-melting paleyellow solid: NMR δ_(H)(400 MHz; d₆-DMSO) 1.08 (6H, d, J 6.5 Hz), 1.40(9H, s), 2.21 (3H, s), 2.41 (3H, s), 2.48-2.52 (2H, m), 3.68-3.85 (2H,br d, J 12 Hz), 3.95-4.06 (2H, m), 4.97 (2H, s), 5.07 (2H, s) and6.83-6.92 (2H, m); HPLC (XTERRA, 50/80, 220 nm) 85.7% (6.26 min).

[0731] cis-2,6-Dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl esterfumarate:a solution of HCl in dioxane (4 M; 2.3 mL, 10 eq) was added to asolution cis-2,6-dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester (463 mg,0.91 mmol) in methanol (15 mL) and the resultant mixture was stirred atambient temperature for 8 h. The solvent was removed in vacuo and theresidue was suspended in aqueous sodium hydroxide solution (2 N; 30 mL)and extracted with diethyl ether (2×20 mL) and ethyl acetate (1×20 mL).The combined organics were washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo to afford the free-base (195 mg) as a pale yellowsolid. This material was dissolved in hot IPA (3 mL) and added to astirred solution of fumaric acid (78 mg, 1.5 eq) in hot IPA (2 mL). Theresultant suspension was allowed to cool to ambient temperature, thencooled in ice-water. Diethyl ether (5 mL) was added and the suspensionwas heated to give a solution, then allowed to cool. The resultantsolution was cooled in ice-water and filtration afforded the desiredproduct (155 mg, 32%) as a white, crystalline solid: NMR δ_(H)(400 MHz;d₆-DMSO) 1.17 (6H, d, J 7.0 Hz), 2.21 (3H, s), 2.41 (3H, s), 2.71 (2H,dd, J 12.5, 4.5 Hz), 2.77 (2H, d, J 12.5 Hz), 3.88-3.96 (2H, m), 4.97(2H, s), 5.06 (2H, s), 6.58 (2H, s) and 6.83-6.91 (2H, m); HPLC (XTERRA,50/80, 220 nm) 99% (2.39 min).

Example 122

[0732] 2-Fluoro-5-(2-methylpropyl)-oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 1-iodo-2-methylpropane and1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to themethods described for Examples 54 and 96 to give the product as a whitesolid (31.3%); melting point 178.6-178.7° C.; NMR δ_(H) (400 MHz,DMSO-d₆) 0.961(6H, d, J 7.0 Hz), 1.193(6H, d, J 7.0 Hz), 1.994(1H, m, J6.5 Hz), 2.726(4H, bm), 3.709(2H, d J 6.5 Hz), 3.966(2H, q), 5.084(2H,s), 6.593(2H, s), 6.933(2H, m) and 7.124(1H, t, J 9.0 Hz).

Example 123

[0733] 2-Chloro-6-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride was prepared from 2-chloro-6-fluorobenzyl alcohol and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 52 and 54 to give theproduct as a white solid (0.2713 g, 80% overall); (Found: C, 49.8; H,5.7; N, 8.0%. C₁₄H₁₈ClN₂O₂.HCl requires C, 49.9; H, 5.7; N, 8.3%); δ_(H)(400 MHz, DMSO-d₆) 10.01 (1H, br), 9.27 (1H, br), 7.49 (1H, m, J 8.0Hz), 7.40 (1H, d, J 8.0 Hz), 7.30 (1H, t, J 9 Hz), 5.22 (2H, d, J 1.6Hz), 4.24 (2H, m, J 6.5 Hz), 3.17-3.06 (4H, m), and 1.28 (6H, d, J 7.2Hz).

Example 124

[0734] (R)-2,6-Difluorobenzyl 2-methylpiperazine-1-carboxylatehydrochloride was prepared from 2,6-difluorobenzyl alcohol and(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 52 and 54 to give the product as awhite solid (0.217 g, 70% overall); (Found: C, 50.7; H, 5.65; N, 9.0.C₁₃H₁₆F₂N₂O₂.HCl requires C, 50.9; H, 5.6; N, 9.1%); δ_(H) (400 MHz,DMSO-d₆) 9.39 (2H, br), 7.50 (1H, m), 7.18-7.12 (2H, m), 5.17 (2H, m, J12.4 Hz), 4.29 (2H, m), 3.88 (1H, d, J 13 Hz), 3.24-3.03 (4H, m, J 13Hz), 2.86 (1H, m, J 12.4 Hz), and 1.24 (3H, d, J 7.2 Hz).

Example 125

[0735] (R,R)-4-Difluoromethoxybenzyl2,6-dimethylpiperazine-1-carboxylate

[0736] (S) N-Benzyl-1-amino-2-propanol hydrochloride: a mixture of (S)1-amino-2-propanol (9.0 g), benzaldehyde (14.7 ml), magnesium sulfateand THF (200 ml) was stirred for 18 h then filtered and concentrated invacuo. The residue was dissolved in ethanol (200 ml) and sodiumborohydride (1.1 g) was added. The mixture was stirred for 2 h then afurther portion of sodium borohydride (1.1 g) was added. The mixture wasstirred for 18 h then concentrated in vacuo. The residue was partitionedbetween dilute hydrochloric acid (2M, 200 ml) and ether (100 ml). Theaqueous layer was basified with sodium hydroxide solution and extractedwith two portions of ethyl acetate (100 ml). The combined ethyl acetatelayers were washed (water), dried (sodium sulfate) and concentrated invacuo. The residue was dissolved in ether (50 ml) and HCl-dioxane (4M,35 ml) was added dropwise. The precipitate was filtered off, washed withether and dried to give the product as a white solid (17.0 g); 8 H (400MHz, DMSO-d₆) 9.43 (1H, m), 9.12 (1H, m), 7.58 (2H, dd, J 7.5, 2 Hz),7.45-7.39 (3H, m), 5.35 (1H, m), 4.14 (2H, s), 4.01 (1H, m), 2.87 (1H,d, J 12 Hz), 2.67 (1H, t, J 8.5 Hz) and 1.08 (3H, d, J 6 Hz); HPLC[XTERRA; NH₄OAc_((aq))—MeOH (9:1)] 97% (1.08 min).

[0737] (S) N-Benzyl-1-amino-2-propanol (R) N-tert-butoxycarbonyl-alanineamide: carbonyldiimidazole (12.1 g) was added to a stirred solution of(R) N-tert-butoxycarbonyl-alanine (14.1 g) in DCM (200 ml). The mixturewas stirred for 90 min then (S) N-benzyl-1-amino-2-propanolhydrochloride (15.0 g) was added portionwise. The mixture was stirredfor 96 h then concentrated in vacuo. The residue was purified by flashcolumn chromatography [SiO₂; ethyl acetate—isohexane(1:1)] to give theproduct as a gum (11.5 g); δ_(H) (400 MHz, CDCl₃) 7.39-7.16 (5H, m),5.37 (1H, m), 4.90-4.55 (3H, m), 4.09 (0.5H, m), 3.97 (0.5H, m), 3.59(1H, m), 3.42 (1H, m), 3.22 (1H, m), 1.44 (4.5H, s), 1.42 (4.5H, s),1.36 (1.5H, d, J 6.5 Hz), 1.26 (1.5H, d, J 6.5 Hz), 1.20 (1.5H, d, J 6Hz) and 1.12 (1.5H, d, J 6 Hz); HPLC (XTERRA, 50/80, 220 nm) 97% (1.77min).

[0738] (R,R)1-Benzyl-3,5-dimethylpiperazine-2-one: trifluoroacetic acid(50 ml) was added dropwise to a stirred solution of(S)N-benzyl-1-amino-2-propanol (R)N-tert-butoxycarbonyl-alanine amide(10.7 g) in DCM (100 ml) at 0° C. The mixture was stirred for 2 h thenconcentrated in vacuo. The residue was partitioned between sodiumhydroxide solution (2M, 200 ml) was dichloromethane (200 ml). Theorganic layer was washed (water), dried (sodium sulfate) andconcentrated in vacuo to give a viscous oil (7.15 g). To the oil wereadded triphenylphosphine (9.4 g) and THF (150 ml) and the stirredmixture was cooled to 0° C. under Ar. To the stirred solution was addeddi-tert-butyldiazodicarboxylate (8.6 g). The mixture was warmed to roomtemperature, stirred for 18 h then concentrated in vacuo. Dilutehydrochloric acid (1M, 100 ml) and conc. hydrochloric acid (10 ml) wereadded to the mixture. The mixture was stirred for 3 h then filtered. Thefiltrate was washed with ether (50 ml) then made basic using sodiumhydroxide solution and extracted with two portions of ethyl acetate (100ml). The combined ethyl acetate extracts were washed (water, brine),dried (sodium sulfate), concentrated in vacuo and purified by flashcolumn chromatography [SiO₂; ethyl acetate—methanol—NH₄OH(95:5)→(79:20:1)] to give the product as clear oil (1.38 g); 67 _(H)(400 MHz, CDCl₃) 7.35-7.22 (5H, m), 4.66 (1H, d, J 14.5 Hz), 4.49 (1H,d, J 14.5 Hz), 3.78 (1H, q, J 7 Hz), 3.33 (1H, m), 3.16 (1H, dd, J 12, 4Hz), 2.97 (1H, dd, J 12,9 Hz) and 1.49 (3H, d, J 7 Hz); LC 96%, 0.67min.

[0739] (R,R)1-Benzyl-3,5-dimethylpiperazine: a solution of(R,R)1-benzyl-3,5-dimethylpiperazine-2-one (1.3 g) in THF (10 ml) wasadded dropwise to a stirred suspension of lithium aluminium hydride(0.68 g) in THF (30 ml) at 0° C. under Ar. The mixture was stirred for30 min then heated under reflux for a further 18 h. The mixture wascooled to 0° C. and diluted with ether (50 ml). To the stirred mixturewere added water (2 ml) sodium hydroxide solution (2 ml) and water (2ml). The mixture was stirred for 1 h then filtered through a pad ofkieselguhr, washing with DCM. The filtrate was concentrated in vacuo togive the product as a clear oil (0.99 g); δ_(H) (400 MHz, CDCl₃)7.35-7.20 (5H, m), 3.48 (1H, d, J 13 Hz), 3.38 (1H, d, J 13 Hz), 3.19(1H, m), 2.49 (2H, dd, J 10.5, 3 Hz), 2.09 (2H, dd, J 10, 6.5 Hz) and1.14 (6H, d, J 6.5 Hz); LC 93%, 1.91 min.

[0740] (R,R)2,6-Dimethylpiperazine dihydrochloride: a mixture of(R,R)4-Benzyl-2,6-dimethylpiperazine (0.95 g), palladiumhydroxide/carbon (20%, 0.35 g) and methanol (30 ml) was shaken underhydrogen (45 p.s.i.) for 18 h. The mixture was filtered through a pad ofkieselguhr, washing with methanol. The filtrate was treated withHCl-dioxane (4M, 5 ml), left to stand for 30 min then concentrated invacuo. The residue was crystallised under diisopropyl ether to give theproduct as an off-white crystalline solid (0.17 g); δ_(H) (400 MHz,DMSO-d₆) 10.02-9.72 (4H, m), 3.72 (2H, m), 3.33 (2H, dd, J 13.5, 4 Hz),3.15 (2H, dd, J 13.5, 7 Hz) and 1.40 (6H, d, J 7 Hz); δ_(C) (167 MHz,DMSO-d₆) 43.8, 43.7 and 14.3.

[0741](R,R)1-Chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine; to astirred mixture of (R,R)2,6-dimethylpiperazine dihydrochloride (0.50 g)and triethylamine (0.93 ml) in DCM (50 ml) at 0° C. was added dropwise asolution of di-tert-butyl-dicarbonate (0.58 g) in DCM (5 ml). Themixture was warmed to room temperature, stirred for 2 h thenconcentrated in vacuo. The residue was dissolved in ethyl acetate,filtered through a PTFE membrane and concentrated in vacuo to give aclear oil (0.47 g). To the oil were added pyridine (0.6 ml) and DCM (6ml). The mixture was added dropwise to a stirred solution of triphosgene(0.25 g) in DCM (20 ml) at 0° C. The mixture was stirred for 1 h, washedwith two portions of water (20 ml) then dried over sodium sulfate andconcentrated in vacuo to give the product as a yellow oil (0.43 g);δ_(H) (400 MHz, CDCl₃) 4.29 (1.6H, m), 4.07 (0.4H, m), 3.62 (2H, m),3.54 (2H, m), 1.49 (7H, s), 1.48 (2H, s), 1.37 (2.5H, m) and 1.23 (0.5H,m).

[0742] (R,R)4-Difluoromethoxybenzyl-2,6-dimethylpiperazine-1-carboxylatefumarate was prepared from(R,R)1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.20g) and 4-difluoromethoxybenzyl alcohol (0.13 g) according to theprocedures described for Example 48 to give the product as a white solid(0.14 g); δ_(H) (400 MHz, DMSO-d₆) 7.43 (2H, d, J 9 Hz), 7.23 (1H, t, J74 Hz), 7.18 (2H, d, J 9 Hz), 6.53 (2H, s), 5.10 (1H, d, J 12.5 Hz),5.03 (1H, d, J 12.5 Hz), 3.92 (2H, m), 3.16 (2H, dd, J 13, 4 Hz), 2.84(2H, dd J 12.5, 3.5 Hz) and 1.23 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80,220 nm) 96% (1.22 min).

Example 126

[0743] (R)-2-Fluoro-5-(2-propenyl)oxybenzyl2-methylpiperazine-1-carboxylate

[0744] In a sealed 7 mL glass vial a mixture of 2-fluoro-5-hydroxybenzylalcohol (50 mg, 0.35 mmol), PS-BEMP (2 g, 2.2 mmol/g, 0.46 mmol) andacetonitrile (3 mL) was shaken for 30 minutes. allyl bromide (18 uL,0.22 mmol) was added and the mixture was shaken for 18 h. The mixturewas filtered through a PTFE frit, washing with dichloromethane. Thefiltrate was concentrated under vacuum to give the product as acolourless oil which was used without further purification.

[0745] To a stirred solution of disuccinimidyl carbonate (3 mmol) inacetonitrile (18 mL) was added 2-fluoro-5-(2-propenyl)benzyl alcohol (3mmol) then triethylamine (6 mmol). The mixture was stirred for 150minutes at room temperature. To a polypropylene 10 mL tube weresequentially added (R)2-methylpiperazine loaded resin (0.2 g, 0.05 mmol)and a portion of the benzyl alcohol/DSC mixture (3 mL, 5 mmol). Themixture was heated to 60° C. and agitated for 16 h. The mixture wascooled to room temperature then drained. The resin was washed 3× eachwith THF, methanol and dichloromethane using the following automatedsequence: 5 mL solvent added, wash for 5 minutes, drain for 2 minutes.To the washed resin was added 5% trifluoroacetic acid in dichloromethane(5 mL). The mixture was agitated for 1 h then drained. More TFA/DCM (5mL) was added and the mixture was agitated for a further hour thendrained again. The combined TFA/DCM washes were concentrated undervacuum to give the product as a pale brown solid (7.5%); HPLC (XTERRA,50/80, 220 nm) 86.2% (1.91 min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.149(3H,d, J 7.0 Hz), 2.455(1H, td, J 3.5, 8.5 Hz), 2.676(2H, d, J 3.0 Hz),2.834(1H, bdd), 2.938(1H, td), 3.645(1H, dd), 4.045(1H, m), 4.542(2H,dt, J 1.5, 5.5 Hz), 5.064(2H, m), 5.240(1H, m), 5.380(1H, m), 6.020(1H,m), 6.937(2H, m) and 7.136(1H, t, J 9.0 Hz).

Example 127

[0746] 2-Fluoro-5-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, allyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (8.4%); HPLC (XTERRA, 50/80, 220 nm) 95.7% (2.87min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.183(6H, d, J 6.5 Hz), 2.673(4H, m),3.294(2H, bs), 3.910(2H, m), 4.572(2H, m), 5.078(2H, s), 5.252(1H, m),5.371(1H, m), 6.022(1H, m), 6.948(2H, m) and 7.138(1H, t, J 9.5 Hz).

Example 128

[0747] 5-Cyclohexylmethoxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, cyclohexylmethyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (10.8%); HPLC (XTERRA, 50/80, 220 nm) 91.4%(6.77 min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.016(2H, m), 1.204(8H, m),1.735(5H, m), 2.681(4H, m), 3.291(2H, s) 3.737(2H, d, J 6.5 Hz),3.905(2H, m) 5.078(2H, s), 6.931(2H, m) and 7.119(1H, t, J 9.0 Hz).

Example 129

[0748] 2-Fluoro-5-(2-phenyl)ethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 2-phenylethyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (2.2%); HPLC (XTERRA, 50/80, 220 nm) 87.7% (5.58min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.168(6H, d, J 7.0 Hz), 2.685(4H, m),3.020(2H, t, J 7.0 Hz), 3.915(2H, m), 4.175(2H, t, J 7.0 Hz), 5.079(2H,s), 6.940(2H, m), 7.132(1H, t, J 9.0 Hz), 7.224(1H, m) and 7.308(4H, m).

Example 130

[0749] 2-Fluoro-5-(3-phenyl)propoxybenzyl piperazine-1-carboxylate wasprepared from 2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl bromideand piperazine resin according to the methods described for Example 126to give the product as a yellow oil (12.8%); HPLC (XTERRA, 50/80, 220nm) 95.6% (5.30 min); NMR δ_(H) (400 MHz, DMSO-d₆) 2.006 (2H, m), 2.621(4H, bs), 2.727 (2H, t, J 7.5 Hz), 3.282 (5H, bt), 3.936 (2H, t, J 6.5Hz), 5.068 (2H, s), 6.932 (2H, m) and 7.167 (6H, m).

Example 131

[0750] (R)-2-Fluoro-5-(3-phenyl)propoxybenzyl2-methylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl bromide and(R)-2-methylpiperazine resin according to the methods described forExample 126 to give the product as a yellow oil (6.5%); HPLC (XTERRA,50/80, 220 nm) 89.0% (5.68 min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.142 (3H,d. J 7.0 Hz), 2.001 (2H, m), 2.439 (1H, m), 2.657 (2H, m), 2.730 (2H, t,J 6.5 Hz), 2.845 (1H, bd), 2.930 (2H, bt), 3.633 (1H, bd), 3.939 (2H, t,J 6.5 Hz), 4.010 (1H, m), 5.065 (2H, m), 6.922 (2H, m) and 7.207 (6H,m).

Example 132

[0751] 2-Fluoro-5-(3-phenyl)propoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (2.3%); HPLC (XTERRA, 50/80, 220 nm) 91.1% (6.29min); NMR δ_(H) (400 MHz, DMSO-d₆) 7.32-7.10 (6H, m), 6.95 (1H, q, J 3Hz), 6.91 (1H, dt, J 9, 4Hz), 5.08 (2H, s), 3.93 (2H, t, J 6.5 Hz), 3.91(2H,m), 2.73 (2H, t, J 7 Hz), 2.71 (2H, d, J 8.5 Hz), 2.65 (2H, dd, J12.5, 4.5 Hz), 2.00 (2H, m) and 1.18 (6H, d, J 7 Hz).

Example 133

[0752] 2-Fluoro-5-(3-trifluoromethylbenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 3-trifluoromethylbenzyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (10.5%); HPLC (XTERRA, 50/80, 220 nm) 96.9%(6.20 min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.164(6H, d, J 6.5 Hz),2.668(4H, m), 3.889(2H, m), 5.082(2H, s), 5.199(2H, s), 7.057(2H, m),7.175(1H, t, J 6.5 Hz) and 7.688(4H, m).

Example 134

[0753] 2-Fluoro-5-(2-pyridylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 2-pyridylmethyl chloride hydrochlorideand 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (10.4%); HPLC (XTERRA, 50/80, 220 nm) 91.1%(2.02 min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.174 (6H, d, J 6.5 Hz), 2.676(4H, m), 3.902 (2H, m), 5.069 (2H, s), 5.165 (2H, s), 7.018 (2H, m),7.161 (1H, t, J 9.0 Hz), 7.350 (1H, m), 7.493 (1H, d, J 7.0 Hz), 7.825(1H, m) and 8.575 (1H, m).

Example 135

[0754] 2-Fluoro-5-(3-pyridylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 3-pyridylmethyl chloride hydrochlorideand 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Examples 54 and 121 to give theproduct as a yellow oil (5.4%); HPLC (XTERRA, 50/80, 220 nm) 91% (1.64min); δ_(H) (400 MHz, DMSO-d₆) 1.172 (6H, d, J 7.0 Hz), 2.673 (4H, m),3.294 (3H, s), 3.900 (2H, m), 5.075 (2H, s), 5.138 (2H, s), 7.052 (2H,m), 7.172 (1H, t, J 9.0 Hz), 7.424 (1H, m), 7.849 (1H, m), 8.546 (1H, m)and 8.654 (1H, m).

Example 136

[0755] (+/−)-2,6-Difluoro-4-(2-pyridylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 2-pyridylmethyl chloridehydrochloride and (+/−)2-methylpiperazine resin according to the methodsdescribed for Example 126 to give the product as a yellow oil: δ_(H)(400 MHz, DMSO-d₆) 1.19 (3H, d, J 7.1 Hz), 2.85 (1H, m), 3.05-3.20 (4H,m), 3.90 (1H, m), 4.35 (1H, m), 5.10 (2H, m), 5.28 (2H, s), 6.92 (2H,m), 7.48 (1H, m), 7.62 (1H, m), 7.96 (1H, m), 8.65 (1H, m) and 9.15 (1H,br); HPLC (XTERRA, 50/80, 220 nm) 92% (1.35 min).

Example 137

[0756] (+/−)-2,6-Difluoro-4-(3-pyridylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 3-pyridylmethyl chloridehydrochloride and (+/−)2-methylpiperazine resin according to the methodsdescribed for Example 126 to give the product as a yellow oil: δ_(H)(400 MHz, DMSO-d₆) 1.19 (3H, d, J 7.1 Hz), 2.85 (1H, m), 3.05-3.20 (4H,m), 3.90 (1H, m), 4.35 (1H, m), 5.10 (2H, m), 5.28 (2H, s), 6.92 (2H,m), 7.78 (1H, m), 8.25 (1H, m), 8.78 (1H, m), 8.84 (1H, m) and 9.20 (1H,br); HPLC (XTERRA, 50/80, 220 nm) 90.5% (1.12 min).

Example 138

[0757] (+/−)-2-Methyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester wasprepared from 2,6-difluoro-4-hydroxybenzyl alcohol,4-(3,5-dimethylisoxazolylmethyl chloride and (+/−)2-methylpiperazineresin according to the methods described for Example 126 to give theproduct as a yellow oil: δ_(H) (400 MHz, DMSO-d₆) 1.20 (3H, d, J 7.1Hz), 2.22 (3H, s), 2.42 (3H, s), 2.85 (1H, m), 3.05-3.20 (4H, m), 3.90(1H, m), 4.35 (1H, m), 5.0 (2H, s), 5.10 (2H, m), 6.89 (2H, m), 8.60(1H, br) and 9.20 (1H, br); HPLC (XTERRA, 50/80, 220 nm) 87.7% (1.61min).

Example 139

[0758] 5-tert-Butylaminocarbonyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride

[0759] 2-Fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzyl alcohol: to astirred mixture of 2-fluoro-5-hydroxybenzaldehyde (0.28 g),N,N-di-isopropylethylamine (0.52 ml) and DCM (2 ml) at 0° C. was addeddropwise 2-(trimethylsilyl)ethoxymethyl chloride (0.45 ml). The mixturewas stired 1 h then partitioned between DCM (25 ml) and water (25 ml).The organic layer was washed (water, brine), dried (sodium sulfate) andconcentrated in vacuo. The residue was dissolved in 2-propanol (20 ml)and sodium borohydride (0.15 g) was added. The mixture was stirred 1 hthen partitioned between isopropyl ether (2×50 ml) and water (50 ml).The combined organics were washed (water), concentrated in vacuo andpurified by column chromatography [SiO₂; DCM-isopropyl ether(1:0→0:1)]to give the product as a colourless oil (0.54 g, 99%) which was usedwithout further purification.

[0760]2-Fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylatewas prepared from 2-fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzylalcohol and1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the procedures described for Example 54 to give the product as aclear oil which was used immediately without further purification.

[0761] 2-Fluoro-5-hydroxybenzyl-cis-2,6-dimethylpiperazine-1-carboxylatehydrochloride: a mixture of crude2-fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate(0.61 g) hydrogen chloride solution (4.0 M, dioxane, 2 ml) and methanol(4 ml) was stirred for 3 h then concentrated in vacuo. The residue wasleft to stand under ether (10 ml) for 1 h; the white precipitate wasfiltered off, washed with ether and dried to give the product as a whitesolid (0.23 g, 71%): δ_(H) (400 MHz, DMSO-d₆) 9.84 (1H, br), 9.51 (1H,br), 9.15 (1H, br), 7.01 (1H, t, J 9 Hz), 6.81 (1H, dd, J 6, 3 Hz), 6.73(1H, m), 5.08 (2H, s), 4.30 (2H, m), 3.16 (2H, d, J 11 Hz), 3.10 (2H, m)and 1.30(6H, d, J 7 Hz).

[0762]2-Fluoro-5-hydroxybenzyl-cis-2,6-dimethyl-4-tert-butylcarbonylpiperazine-1-carboxylate:to a stirred solution of2-fluoro-5-hydroxybenzyl-cis-2,6-dimethylpiperazine-1-carboxylate(free-base, 1.93 g) in DCM (70 ml) was added dropwise di-tert-butyldi-carbonate (1.68 ml). The mixture was stirred for 18 h thenconcentrated in vacuo and purified by column chromatography [SiO₂;isopropyl ether—isohexane (2:3→1:0)] to give the product as a whitesolid (2.24 g, 84%): δ_(H) (400 MHz, DMSO-d₆) 6.92 (1H, t, J 9 Hz), 6.87(1H, m), 6.76 (1H, m), 6.10 (1H, m, OH), 5.15 (2H, s), 4.20 (2H, t, J5.5 Hz), 3.93 (2H, m), 2.97 (2H, m), 1.48 (9H, s) and 1.23 (6H, d, J 7Hz); HPLC XTERRA, 50-80%, 220 nm, 98.5% (4.86 min).

[0763]5-tert-Butylaminocarbonyloxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate:triethylamine (0.02 ml) was added to a stirred mixture of2-fluoro-5-hydroxybenzyl-cis-2,6-dimethyl-4-tert-butylcarbonylpiperazine-1-carboxylate(0.19 g) and tert-butylisocyanate (0.12 ml) in DCM (2 ml). The mixturewas stirred 18 h the concentrated in vacuo and purified by columnchromatography [SiO₂: isopropyl ether—isohexane (2:3→1:0)] to give theproduct as a colourless partially solidified gum (0.2445 g, 102%). Rf(Silica, isopropyl ether) 0.20; δ_(H) (400 MHz, CDCl₃) 7.14 (1H, m),7.06-7.03 (2H, m), 5.18 (2H, s), 4.98 (1H, br), 4.20 (2H, br), 3.96 (1H,br), 3.87 (1H, br), 3.00 (1H, br), 2.93 (1H, br), 1.48 (9H, s), 1.38(9H, s), and 1.24 (6H, d, J 6.4 Hz).

[0764] 5-tert-Butylaminocarbonyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from5-tert-butylaminocarbonyloxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylateaccording to the method described for Example 52 to give the product asa white solid (0.1538 g, 72% overall); (Found: C, 54.4; H, 7.0; N, 9.9%.C₁₉H₂₈FN₃O₄.HCl requires C, 54.6; H, 7.0; N, 10.05%); δ_(H) (400 MHz,DMSO-d₆) 9.8 (1H, br), 9.2 (1H, br), 7.64 (1H, s), 7.24 (1H, t, J 9.2Hz), 7.18 (1H, m), 7.11 (1H, br), 5.15 (2H, s), 4.30 (2H, m, J 6 Hz),3.16 (2H, d, J 13 Hz), 3.07 (2H, dd, J 5 and 13 Hz), and 1.30-1.27 (15H,m).

Example 140

[0765] 2-Fluoro-5-(4-difluoromethoxybenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from2-fluoro-5-hydroxybenzyl alcohol, 4-difluoromethoxybenzyl chloride and1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Examples 52 and 54 to give the product as awhite solid (0.224 g, 94% overall); (Found: C, 55.7; H, 5.7; N, 5.9.C₂₂H₂₅F₃N₂O₄.HCl requires C, 55.6; H, 5.5; N, 5.9%); δ_(H)(400 MHz,DMSO-d₆) 9.8 (1H, br), 9.3 (1H, br), 7.50 (2H, d, J 8.4 Hz), 7.26(1H, t,J 74 Hz), 7.21-7.15 (3H, m), 7.09 (1H, m), 7.03 (1H, m, J 3.2 Hz), 5.12(2H, s), 5.08 (2H, s), 4.28 (2H, m, J 6 Hz), 3.15 (2H, d, J 13 Hz), 3.06(2H, dd, J 5 and 13 Hz), and 1.29 (6H, d, J 7.2 Hz).

Example 141

[0766] Piperazine-1-carboxylic acid2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzylester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole and piperazine resinaccording to the methods described for Example 126 to give the productas a yellow oil: δ_(H) (400 MHz; d₆-DMSO) 2.60 (4H, br s), 3.30 (4H, brs), 5.04 (2H, s), 5.42 (2H, s), 6.92-7.01 (2H, m), 7.36 (1H, dd, J 5.0,4 Hz), 8.06 (1H, dd, J 4, 1 Hz) and 8.12 (1H, dd, J 5.0, 1 Hz); HPLC(XTERRA, 50-80%, 235 nm) 99.4% (3.71 min).

Example 142

[0767] (R)-2-Methyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzylester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole and(R)2-methylpiperazine resin according to the methods described forExample 126 to give the product as a yellow oil: δ_(H)(400 MHz; d₆-DMSO)1.10 (3H, d, J 7.0 Hz), 2.40 (1H, td, J 12.0, 3.5 Hz), 2.62 (2H, br d,J, 2.5 Hz), 2.75-2.82 (1H, br d, J 12 Hz), 2.88 (1H, td, J 12.5, 3.5Hz), 3.55 (1H, br d, J12 Hz), 3.96 (1H, br s), 5.02 (1H, d, J 12.5 Hz),5.07 (1H, d, J 12.5 Hz), 5.42 (2H, s), 6.93-7.01 (2H, m), 7.36 (1H, dd,J 5.0 and 4 Hz), 8.06 (1H, dd, J 4, 1.0 Hz) and 8.12 (1H, dd, J 5.0, 1Hz); HPLC (XTERRA, 50-80%, 235 nm) 99.8% (4.22 min).

Example 143

[0768] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzylester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole andcis-1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the methods described for Example 54 and 121 to give theproduct as a yellow oil: δ_(H)(400 MHz; d₆-DMSO) 1.14 (6H, d, J 6.5 Hz),2.60 (2H, dd, J 12, 5 Hz), 2.66 (2H, d, J 12 Hz), 3.77-3.87 (2H, m),5.05 (2H, s), 5.42 (2H, s), 6.93-7.01 (2H, m), 7.36 (1H, dd, J 5.0, 4Hz), 8.06 (1H, dd, J 4,1.0 Hz) and 8.12 (1H, dd, J 5.0, 1.0 Hz); HPLC(XTERRA, 50-80%, 235 nm) 99.4% (5.04 min).

Example 144

[0769] 2,6-Difluoro-4-(3-fluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 3-fluorobenzyl chloride and1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Example 54 and 121 to give the product as ayellow oil: δ_(H) (400 MHz; d₆-DMSO) 1.13 (6H, d, J 7.0 Hz), 2.60 (2H,dd, J 12, 4.5 Hz), 2.66 (2H, d, J 12 Hz), 3.77-3.86 (2H, m), 5.03 (2H,s), 5.18 (2H, s), 6.84-6.93 (2H, m), 7.16-7.22 (1H, m), 7.27-7.32 (2H,m) and 7.42-7.49 (1H, m); HPLC (XTERRA, 50-80%, 220 nm) 99.8% (5.96min).

Example 145

[0770] 2,6-Difluoro-4-(3,4-difluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 3,4-difluorobenzyl chloride and1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Example 54 and 121 to give the product as ayellow oil: δ_(H) (400 MHz; d₆-DMSO) 1.13 (6H, d, J 7.0 Hz), 2.60 (2H,dd, J 12.0, 4.5 Hz), 2.66 (2H, d, J 12.0 Hz), 3.77-3.85 (2H, m), 5.04(2H, s), 5.13 (2H, s), 6.84-6.92 (2H, m), 7.29-7.35 (1H, m), 7.48 (1H,dt, J 11.0, 8.5 Hz) and 7.55 (1H, ddd, J 11.5, 7.5, 2.5 Hz); HPLC(XTERRA, 50-80%, 220 nm) 99.5% (6.17 min).

Example 146

[0771] 2-Fluoro-5-(2,4-difluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 2,4-difluorobenzyl chloride and1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Example 54 and 121 to give the product as ayellow oil: δ_(H) (400 MHz; d₆-DMSO) 1.26 (6H, d, J 6.9 Hz), 2.75-2.90(4H, m), 4.10 (2H, br), 4.98 (2H, s), 5.20 (2H, s), 6.85 (1H, m), 6.98(2H, m) and 7.10-7.30 (3H, m), NH not observed; HPLC (XTERRA, 50/80%,220 nm) 93.8% (5.68 min).

Example 147

[0772] 2-Fluoro-5-(3,4-difluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 3,4-difluorobenzyl chloride and1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine accordingto the methods described for Example 54 and 121 to give the product as ayellow oil: δ_(H) (400 MHz; d6-DMSO) 1.29 (6H, d, J 6.9 Hz), 2.77-2.90(4H, m), 4.10 (2H, br), 5.04 (2H, s), 5.18 (2H, s), 6.80-7.02 (5H, m)and 7.42 (1H, m), NH not observed; HPLC (XTERRA, 50/80%, 220 nm) 89.5%(5.5 min).

Example 148

[0773] 2,6-Difluoro-4-(3-furylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate

[0774] 2,6-Difluoro-4-(furan-3-methoxy)benzyl alcohol: methanesulfonylchloride (0.9 ml) was added dropwise to a stirred solution of3-furan-methanol (1.0 g) and triethylamine (2.1 ml) in dichloromethane(30 ml) at 0° C . The mixture was stirred for 30 min. then warmed toroom temperature and stirred for a further 2 h. The mixture waspartitioned between ether (100 ml) and water (100 ml). The organic layerwas washed (water, brine), dried (sodium sulfate) and concentrated invacuo to give a pale yellow oil (0.77 g). To the oil were added2,6-difluoro-4-hydroxybenzyl alcohol (0.56 g), cesium carbonate (1.1 g)and DMF (30 ml). The mixture was stirred for 18 h then partitionedbetween ethyl acetate (20 ml) and water (50 ml). The layers wereseparated; the aqueous layer was extracted with more ethyl acetate (20ml). The combined organic layers were washed (water, brine), dried(sodium sulfate) and concentrated in vacuo. The residue was purified byflash column chromatography [SiO₂: isohexane—ethyl acetate (3:1)] togive the product as a clear oil (0.16 g); δ_(H) (400 MHz, CDCl₃) 7.51(1H, d, J 1 Hz), 7.45 (1H, t, J 2 Hz), 6.54 (1H t, J 4 Hz), 6.50 (1H, t,J 4 Hz), 6.47 (1H, d, J 1.5 Hz), 4.91 (2H, s) and 4.71 (2H, d, J 6.5Hz); HPLC (XTERRA, 50/80, 220 nm) 1.76 min (74%).

[0775]2,6-Difluoro-4-(3-furanmethoxy)benzyl-2,6-dimethylpiperazine-1-carboxylatefumarate: to a stirred suspension of sodium hydride (60%, 0.015 g) inDMF (1 ml) was added dropwise a solution of2,6-difluoro-4-(furan-3-methoxy)benzyl alcohol (0.06 g) and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.07 g)in DMF (2 ml). The mixture was stirred for 2 h then partitioned betweenethyl acetate (20 ml) and water (20 ml). The organic layer was washed(water, brine), dried (sodium sulfate) and concentrated in vacuo to givea yellow oil (0.11 g). To the residue were added methanol (2 ml) andhydrogen chloride in dioxane (4M, 0.3 ml). The mixture was stirred for 4h then partitioned between water (20 ml) and ether (20 ml). The aqueouslayer was basified with aqueous sodium hydroxide solution (2M, 5 ml) andextracted with ethyl acetate (20 ml). The ethyl acetate layer was washed(water, brine), dried (sodium sulfate) and concentrated in vacuo to givea pale oil (0.036 g). To the oil were added fumaric acid (0.013 g) and2-propanol (1 ml). The mixture was heated to reflux then cooled to roomtemperature and diluted with ether (5 ml). The emerging precipitate wasfiltered-off, washed (ether) and dried to give the product as a whitesolid (0.027 g); δ_(H) (400 MHz, DMSO-d₆) 7.81 (1H, t, J 1.5 Hz), 7.67(1H, t, J 2 Hz), 6.86 (1H, t, J 3 Hz), 6.82 (1H, t, J 3 Hz), 6.59 (2H,s), 6.57 (1H, d, J 1.5 Hz), 5.04 (2H, s), 5.01 (2H, s), 3.95-3.86 (2H,m), 2.80-2.65 (4H, m) and 1.16 (6H, d, J 7 Hz); HPLC (XTERRA, 50/80, 220nM) 82% (4.00 min).

Example 149

[0776] (+/−)-2,6-Difluoro-4-(3-furylmethyl)oxybenzyl2-ethylpiperazine-1-carboxylate fumarate was prepared from1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.07 g),and 2,6-difluoro-4-(furan-3-methoxy)benzyl alcohol (0.06 g) according tothe procedures described for Example 148 to give the product as a whitesolid (0.03 g); □_(H) (400 MHz, DMSO-d₆) 7.81 (1H, d, J 1 Hz), 7.67 (1H,t, J 2 Hz), 6.86 (1H, t, J 3.5 Hz), 6.82 (1H, t, J 3.5 Hz), 6.57 (3H,s), 4.07 (1H, d, J 11 Hz), 5.01 (2H, s), 5.00 (1H, d, J 11 Hz), 3.81(1H, m), 2.91-2.80 (4H, m), 2.74-2.66 (1H, m), 2.59-2.50 (1H, m),1.76-1.63 (1H, m), 1.61-1.48 (1H, m) and 0.73 (3H, t, J 7.5 Hz); HPLC(XTERRA, 50/80, 220 nM) 86% (3.71 min).

Example 150

[0777] (+/−)-Piperazine-1-carboxylic acid2,6-difluoro-4-(tetrahydro-furan-2-ylmethoxy)-benzyl ester fumarate

[0778](+/−)-[2,6-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methanol: astirred mixture of 2,6-difluoro-4-hydroxybenzyl alcohol (0.5 g),(+/−)-tetrahydrofurfuryl bromide (0.36 ml), cesium carbonate (0.56 g)and sodium iodide (0.005 g) in DMF (5 ml) was heated to 60° C. for 18 hthen cooled to room temperature. The mixture was partitioned betweenethyl acetate (30 ml) and aqueous sodium hydroxide solution (2M, 30 ml).The organic layer was washed (water, brine), dried (sodium sulfate) andconcentrated in vacuo. The residue was purified by flash columnchromatography [SiO₂; isohexane—ethyl acetate (4:1)] to give the productas a clear oil (0.17 g); δ_(H) (400 MHz, CDCl₃) 6.50 (1H, t, J 3.5 Hz),6.46 (1H, t, J 3.5 Hz), 4.69 (2H, d, J 6.5 Hz), 4.28-4.21 (1H, m), 3.92(2H, d, J 5 Hz), 3.92 (1H, dd, J 15, 6.5 Hz), 3.83 (1H, dt, J 15, 6.5Hz), 2.12-2.03 (1H, m), 2.00-1.90 (2H, m), 1.83 (1H, t, J 6 Hz) and1.78-1.69 (1H, m); HPLC (XTERRA, 50/80, 220 nM) 98% (0.91 min).

[0779] (+/−)-Piperazine-1-carboxylic acid2,6-difluoro-4-(tetrahydro-furan-2-ylmethoxy)-benzyl ester fumarate wasprepared from 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine (0.076g), and(+/−)-[2,6-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methanol(0.075 g) according to the procedures described for Example 148 to givethe product as a white solid (0.058 g); m.p. 199° C. (decomp.); Found:C, 52.81; H, 5.65; N, 5.78%. C₂₁H₂₆F₂N₂O₈.0.25H₂O requires: C, 52.88; H,5.60; N, 5.87%.

Example 151

[0780] (+/−)-Piperazine-1-carboxylic acid2-fluoro-4-(tetrahydro-furan-2-ylmethoxy)-benzyl ester fumarate

[0781] (+/−)-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methanolwas prepared from 2-fluoro-5-hydroxybenzyl alcohol (0.50 g) and(+/−)-tetrahydrofurfuryl bromide (0.40 ml) according to the proceduredescribed for Example 150 to give the product as a clear oil (0.17 g);δ_(H) (400 MHz, CDCl₃) □_(H) 6.98 (1H, q, J 3 Hz), 6.94 (1H, t, J 9 Hz),6.79 (1H, dt, J 9, 3 Hz), 4.71 (2H, d, J 4.5 Hz), 4.25 (1H, tt, J 7, 5Hz), 3.94 (1H dt, J8.5,6.5 Hz), 3.93 (2H, d, J 5 Hz), 3.82 (1H, dt, J8.5,7 Hz), 2.11-2.03 (1H, m), 2.01-1.88 (2H, m) and 1.80-1.71 (1H, m);HPLC (XTERRA, 50/80, 220 nM) 96% (0.88 min).

[0782] (+/−)-Piperazine-1-carboxylic acid2-fluoro-4-(tetrahydro-furan-2-ylmethoxy)-benzyl ester fumarate wasprepared from(+/−)-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methanol (0.075g) and 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine(0.092 g) using the procedures described in Example 148 to give theproduct as a white, crystalline solid (0.086 g); m.p. 141-147° C.(decomp.); Found: C, 57.01; H, 6.58; N, 5.98%. C₂H₂₇FN₂O₈ requires: C,57.25; H, 6.48; N, 5.81%.

Example 152

[0783] 2,6-Difluoro-4-(3-thienylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate

[0784] [2,6-Difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol: to astirred solution of thiophene-3-methanol (1.0 g) and triethylamine (1.8ml) in DCM (10 ml) at 0° C. was added dropwise methanesulfonyl chloride(0.75 ml). The mixture was warmed to room temperature and stirred for 2h then washed with water (20 ml), filtered through a PTFE membrane andconcentrated in vacuo. To the residue were added2,6-difluoro-4-hydroxybenzyl alcohol (0.5 g), cesium carbonate (0.75 g),sodium iodide (0.01 g) and DMF (5 ml). The mixture was heated to 60° C.and stirred for 18 h. The mixture was cooled to room temperature thenpartitioned between ethyl acetate (40 ml) and water (20 ml). The organiclayer was washed (water), dried (sodium sulfate) and concentrated invacuo. The residue was purified by flash column chromatography [SiO₂;isohexane—ethyl acetate (4:1)] to give the product as a clear oil (0.68g); δ_(H) (400 MHz, CDCl₃) 7.35 (1H, dd, J 5, 3 Hz), 7.31 (1H, m), 7.12(1H, dd, J 5, 1.5 Hz), 6.54 (1H, t, J 3.5 Hz), 6.50 (1H, t, J 3.5 Hz),5.04 (2H, s) and 4.70 (2H, d, J 6 Hz); HPLC (XTERRA, 50/80, 220 nM) 94%(2.51 min).

[0785] 2,6-Difluoro-4-(3-thienylmethyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol (0.15 g) and cis1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.16 g)according to the procedures described in Example 148 to give the productas a white, crystalline solid (0.084 g); m.p. 162-186° C. (decomp.);δ_(H) (400 MHz, DMSO-d₆) 7.61 (1H, m), 7.56 (1H, dd, J 5, 3 Hz), 7.17(1H, dd, J 5, 1 Hz), 5.14 (2H, s), 5.04 (2H, s), 3.90 (2H, m), 2.76 (2H,t, J 11 Hz), 2.68 (2H, dd, J 12, 4.5 Hz) and 1.16 (6H, d, J 7 Hz).

Example 153

[0786] 2,6-Difluoro-4-(3-thienylmethyl)oxybenzylpiperazine-1-carboxylate fumarate was prepared from[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol (0.15 g) and1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine (0.15 g) according tothe procedures described for Example 148 to give the product as a white,crystalline solid (0.084 g); m.p. 161-162° C. (decomp.); δ_(H) (400 MHz,DMSO-d₆) 7.62 (1H, dd, J 3, 1.5 Hz), 7.57 (1H, dd, J 5, 3 Hz), 7.17 (1H,dd, J 5, 1.5 Hz), 6.87 (1H, t, J 3.5 Hz), 6.83 (1H, t, J 3.5 Hz), 6.54(2H, s), 5.14 (2H, s), 5.04 (2H, s), 3.35 (4H, m) and 2.77 (4H, m).

Example 154

[0787] (R)-2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate fumarate was prepared from[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol (0.15 g) and(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine (0.15 g)according to the procedures described for Example 148 to give theproduct as a white, crystalline solid (0.028 g); m.p. 121-143° C.(decomp.); δ_(H) (400 MHz, DMSO-d₆) 7.62 (1H, dd, J 3, 1.5 Hz), 7.57(1H, dd, J 5, 3 Hz), 7.17 (1H, dd, J 5, 1 Hz), 6.87 (1H, t, J 3.5 Hz),6.83 (1H, t, J 3.5 Hz), 6.57 (2H, s), 5.14 (2H, s), 5.07 (1H, d, J 12Hz), 5.01 (1H, d, J 12 Hz), 4.04 (1H, m), 3.63 (1H, m), 3.00-2.86 (3H,m), 2.76 (1H, m), 2.54 (1H, m) and 1.13 (3H, d, J 7 Hz).

Example 155

[0788] (+/−)-2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl2-ethylpiperazine-1-carboxylate fumarate was prepared from[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol (0.15 g) and(+/−)1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine (0.16 g)according to the procedures described for Example 148 to give theproduct as a white, crystalline solid (0.057 g); m.p. 133-134° C.(decomp.); δ_(H) (400 MHz, DMSO-d₆) 7.61 (1H, dd, J 3, 1.5 Hz), 7.56(1H, dd, J 5, 3 Hz), 7.17 (1H, dd, J 4.5, 1 Hz), 5.14 (2H, s), 5.06 (1H,d, J 12 Hz), 5.01 (1H, d, J 12 Hz), 3.92-3.66 (2H, m), 2.94-2.80 (3H,m), 2.76-2.66 (1H, m), 2.62-2.50 (1H, m), 1.78-1.64 (1H, m), 1.63-1.48(1H, m) and 0.72 (3H, d, J 7.5 Hz).

Example 156

[0789] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-methyl-isoxazol-3-ylmethoxy)-benzyl ester was preparedfrom 2,6-difluoro-4-hydroxybenzyl alcohol,3-chloromethyl-5-methyl-isoxazole and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the procedures described for Example 54 and 121 to give theproduct as a yellow oil: δ_(H) (400 MHz; d₆-DMSO) 1.14 (6H, d, J 6.5Hz), 2.41 (H, d, J 1.0 Hz), 2.63 (2H, dd, J 12, 4.5 Hz), 2.68 (2H, d, J12 Hz), 3.80-3.88 (2H, m), 5.04 (2H, s), 5.21 (2H, s), 6.34 (1H, d, J1.0 Hz), and 6.84-6.92 (2H, m); HPLC (XTERRA, 50/80%, 220 nm) 96.8%(2.38 min).

Example 157

[0790] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-benzyl esterwasprepared from 2,6-difluoro-4-hydroxybenzyl alcohol,(5-methyl-3-phenyl-isoxazol-4-yl)-methanol and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the procedures described for Example 54 and 121 to give theproduct as a yellow oil: δ_(H) (400 MHz; d₆-DMSO) 1.15 (6H, d, J 7.0Hz), 2.53 (3H, s), 2.62 (2H, dd, J 12.0, 4.5 Hz), 2.68 (2H, d, J 12.0Hz), 3.80-3.88 (2H, m), 5.01-5.08 (4H, m), 6.84-6.91 (2H, m), 7.48-7.53(3H, m) and 7.64-7.68 (2H, m).

Example 158

[0791] (+/−)-2-Fluoro-5-(2-propenyl)oxybenzyl2-ethylpiperazine-1-carboxylate fumarate was prepared from2-fluoro-5-hydroxybenzyl alcohol, allyl bromide and(+/−)2-ethyl-1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine accordingto the procedures described for Example 148 to give the product as awhite solid (5.1%); HPLC (XTERRA, 50-80%, 220 nm) 96.8% (2.30 min); NMRδ_(H) (400MHz, DMSO-d₆) 0.765 (2H, t, J 7.5 Hz), 1.650 (2H, m), 2.708(1H, m), 2.878 (2H, bt), 3.767 (1H, bd), 3.883 (1H, bs), 4.536 (2H, d, J5.0 Hz), 5.069 (2H, q), 5.247 (1H, bd), 5.377 (1H, bd), 6.013 (1H, bs),6.586 (2H, s), 6.955 (2H, m) and 7.138 (1H, t, J 9.0 Hz).

Example 159

[0792] 2-Fluoro-5-(2-propenyl)oxybenzyl piperazine-1-carboxylatefumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, allylbromide and 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine accordingto the procedures described for Example 148 to give the product as awhite solid (8.5%); HPLC (XTERRA, 50-80%, 220 nm) 98% (1.29 min); NMRδ_(H) (400 MHz, DMSO-d₆) 2.774(4H, bs), 3.381(4H, bs), 4.545(2H, d),5.072(2H, s), 5.251(1H, m), 5.378(1H, m), 6.018(1H, m), 6.557(2H, s),6.964(2H, m) and 7.139(1H, t, J 9.0 Hz).

Example 160

[0793] 2,6-Difluoro-4-(2-thienylmethyl)oxybenzylpiperazine-1-carboxylate fumarate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 2-thiophenemethanol and1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to theprocedures described for Example 152 to give the product as a whitesolid (0.6%); HPLC (XTERRA, 50-80%, 220 nm) 90.6% (3.53 min); NMR δ_(H)(400 MHz, DMSO-d₆) 2.852(4H, bs), 3.400(4H, bs), 5.058(2H, s), 5.354(2H,s), 6.589(6H, s), 6.884(2H, d J 10 Hz), 7.052(1H, m), 7.249(1H, bd) and7.583(1H, dd, J 1.5, 5.0 Hz).

Example 161

[0794] (R)-2,6-Difluoro-4-(2-thienylmethyl)oxybenzyl2-methylpiperazine-1-carboxylate fumarate was prepared from2,6-difluoro-4-hydroxybenzyl alcohol, 2-thiophenemethanol and(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine accordingto the procedures described for Example 152 to give the product as awhite solid (0.24%); HPLC (XTERRA, 50/80%, 220 nm) 100% (4.36 min); NMRδ_(H ()400 MHz, DMSO-d₆) 1.128(3H, d. J 7.0 Hz), 2.931(1H, bm),3.655(4H, bd), 4.073(2H, bs), 5.036(2H, q), 5.340(2H, s), 6.60(4H, s),6.880(1H, d, J 7.0 Hz), 7.05 1(1H, m), 7.248(2H, m) and 7.58 1(1H, m).

Example 162

[0795] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(thiophen-2-ylmethoxy)-benzyl ester fumarate was preparedfrom 2,6-difluoro-4-hydroxybenzyl alcohol, 2-thiophenemethanol and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the procedures described for Example 152 to give theproduct as a white solid (1.8%); HPLC (XTERRA, 50/80%, 220 nm) 94% (5.05min); NMR δ_(H) (400 MHz, DMSO-d₆) 1.160(6H, d, J 7.0 Hz), 2.733(4H,bm), 3.912(2H, bs), 5.042(2H, s), 5.348(2H, s), 6.611(3H, s), 6.884(2H,d, J 10 Hz), 7.050(1H, m), 7.242(1H, m) and 7.582(1H, dd, J 1.5, 5.0Hz).

Example 163

[0796] 5-Butylaminocarbonyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride

[0797]5-Butylaminocarbonyloxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylatewas prepared from5-hydroxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylateand butyl isocyanate according to the method described for Example 139to give the product as a colourless gum (0.177 g, 92%); Rf (Silica,isopropyl ether) 0.175; δ_(H) (400 MHz, CDCl₃) 7.14 (1H, m), 7.07-7.01(2H, m), 5.18 (2H, s), 5.01 (1H, br), 4.20 (2H, br), 3.95 (H, br), 3.26(2H, m, J 7 Hz), 2.96 (2H, br), 1.56 (2H, m, J 7.2 Hz), 1.48 (9H, s),1.39 (2H, m, J 8 Hz), 1.23 (6H, d, J 7.0 Hz), and 0.96 (3H, t, J 7.3Hz).

[0798] 5-Butylaminocarbonyloxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from5-butylaminocarbonyloxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylateaccording to the procedure described in Example 52 to give the productas a white solid (0.1223 g, 85%); (Found: C, 54.6; H, 7.1; N, 9.9%.C₁₉H₂₈FN₃O₄.HCl requires C, 54.6; H, 7.0; N, 10.05%); NMR δ_(H ()400MHz, DMSO-d₆) 9.7 (1H, br), 9.3 (1H, br), 7.76 (1H, t, J 5.6 Hz), 7.24(1H, t, J 9.2 Hz), 7.20 (1H, m), 7.12 (1H, m, J 4.0 Hz), 5.15 (2H, s),4.30 (2H, m), 3.15 (2H, d, J 13 Hz), 3.09-3.02 (4H, m), 1.45 (2H, m, J7.2 Hz), 1.36-1.29 (8H, m, J 7.2 Hz), and 0.89 (3H, t, J 7.2 Hz).

Example 164

[0799] 2-Fluoro-5-(2-propynyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride

[0800]2-Fluoro-5-(2-propynyl)oxybenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylatewas prepared from5-hydroxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylateand propargyl bromide to give the product as a colourless gum (0.191g, >100%). Rf (Silica, isopropyl ether) 0.25; δ_(H) (400 MHz, CDCl₃)7.00-6.98 (2H, m), 6.90 (1H, m), 5.18 (2H, s), 4.66 (2H, d, J 0.24 Hz),4.21 (2H, m, J 5.6 Hz), 3.95 (2H, br), 2.97 (2H, br), 2.51 (1H, t, J0.24 Hz), 1.48 (9H, s), and 1.24 (6H, d, J 6.8 Hz).

[0801] 2-Fluoro-5-(2-propynyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate hydrochloride as prepared from2-fluoro-5-(2-propynyl)oxybenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylateaccording to the procedures described in Example 52 to give the productas a white solid (0.1352 g, 95% overall); ν_(max) (diffusereflectance)/cm−1 3507, 3292, 3242, 2125, 1700, 1594, 1506, and 1209;δ_(H) (400 MHz, DMSO-d₆)10.0-9.0 (2H, br), 7.19 (1H, t, J 9.2 Hz), 7.06(1H, m), 7.00 (1H, m), 5.13 (2H, s), 4.79 (2H, d, J 0.24 Hz), 4.31 (2H,m, J 6 Hz), 3.57 (1H, t, J 0.24 Hz), 3.15 (2H, d, J 13.2 Hz), 3.07 (2H,dd, J 5 and 13.2 Hz), and 1.31 (6H, d, J 7.2 Hz).

Example 165

[0802] 5-(5-[2,1,3]Benzothiadiazolylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 5-[2,1,3]benzothiadiazolylmethylchloride and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the procedures described for Examples 121 and 54 to givethe product as a yellow oil: δ_(H) (400 MHz, DMSO-d₆) 1.25 (6H, d, J 7.0Hz), 2.78-2.95 (4H, m), 4.10 (2H, br), 5.20 (2H, s), 5.22 (2H, s),6.90-7.08 (3H, m), 7.65 (1H, m) and 8.03 (2H, m), NH not observed; HPLC(XTERRA, 50/80%, 220 nm) 90.7% (4.84 min).

Example 166

[0803] 2-Fluoro-5-(3-fluorobenzyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate was prepared from2-fluoro-5-hydroxybenzyl alcohol, 3-fluorobenzyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the procedures described for Examples 121 and 54 to givethe product as a yellow oil: δ_(H) (400 MHz, DMSO-d₆) 1.28 (6H, d, J 6.9Hz), 2.77-2.90 (4H, m), 4.10 (2H, br), 5.03 (2H, s), 5.17 (2H, s), 6.85(1H, m), 6.95-7.10 (3H, m), 7.15 (2H, m) and 7.35 (1H, m), NH notobserved; HPLC (XTERRA, 50/80%, 220 nm) 85% (4.83 min).

Example 167

[0804] (R)-2-Fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylatewas prepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodopentane and(R)2-methylpiperazine resin according to the procedures described forExample 126 to give the product as a yellow oil: δ_(H) (400 MHz,DMSO-d₆) 0.89 (3H, t, J 7.0 Hz), 1.24 (3H, d, J 7.1 Hz), 1.30-1.45 (4H,m), 1.70 (2H, pent, J 6.7 Hz), 2.90 (1H, m), 3.0-3.20 (4H, m), 3.92 (3H,m), 4.38 (1H, m), 5.07 (1H, d, J 12.5 Hz), 5.12 (1H, d, J 12.5 Hz), 6.93(1H, m), 6.98 (1H, m), 7.14 (1H, m), 8.90 (1H, br) and 9.40 (1H, br);HPLC (XTERRA, 50/80%, 220 nm) 84.6% (4.85 min).

Example 168

[0805] 5-(Cyclopropylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from2-fluoro-5-hydroxybenzyl alcohol, cyclopropylmethyl bromide and1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazineaccording to the procedures described for Examples 121 and 54 to givethe product as a white solid: δ_(H)(400 MHz, DMSO-d₆) 7.13 (1H, t, J 9Hz), 6.95 (1H, q, J 3 Hz), 6.90 (1H, dt, J 9, 3.5 Hz), 6.58 (2H, s),5.08 (2H, s), 3.98 (2H, m), 3.78 (2H, d, J 7 Hz), 2.80 (2H, d, J 12 Hz),2.72 (2H, dd, J 12, 4.5 Hz), 1.20 (6H, d, J 7 Hz), 0.56 (2H, ddd, J 8,6, 4.5 Hz) and 0.30 (2H, dt, J 6, 4.5 Hz).

Example 169

[0806] (R)-2-Methyl-piperazine-1-carboxylic acid2-fluoro-5-(2-thiophen-2-yl-ethoxy)-benzyl ester fumarate

[0807] 2-Fluoro-5-[2-(2-thienyl)]ethoxybenzyl alcohol was prepared from2-thiophene-ethanol (0.5 g) and 2-fluoro-5-hydroxybenzyl alcoholaccording to the procedure described in Example 152 to give the productas a clear oil (0.12 g); δ_(H) (400 MHz, CDCl₃) 7.16 (1H, dd, J 5, 1.5Hz), 6.98-6.92 (3H, m), 6.91 (1H, m), 6.78 (1H, dt, J 9, 3.5 Hz), 4.70(2H, d, J 6 Hz), 4.15 (2H, t, J 6.5 Hz) and 3.28 (2H, dt, J 6.5, 1 Hz);HPLC (XTERRA, 50/80%, 220 nm) 97% (3.49 min).

[0808] (R)-2-Methyl-piperazine-1-carboxylic acid2-fluoro-5-(2-thiophen-2-yl-ethoxy)-benzyl ester fumarate was preparedfrom 2-fluoro-5-[2-(2-thienyl)]ethoxybenzyl alcohol and(R)1-chlorocarbonyl-2-methyl 4-tert-butoxycarbonylpiperazine accordingto the procedures described in Example 152 to give the product as awhite, crystalline solid (0.047 g); δ_(H) (400 MHz, DMSO-d₆) 7.53 (1H,dd, J 5, 1 Hz), 7.25-7.09 (3H, m), 7.02 (1H, m), 6.91 (1H, m), 6.58 (2H,s), 4.74 (2H, s), 4.56 (2H, s), 4.26 (1H, m), 3.82 (1H, m), 3.14 (1H,m), 3.00 (1H, m), 2.91-2.80 (2H, m), 2.67 (1H, m) and 1.28 (3H, d, J 6.5Hz); HPLC (XTERRA, 50/80%, 220 nm) 99% (4.15 min).

Example 170

[0809] cis-2,6-Dimethyl-piperazine-1-carboxylic acid3-bromo-2,6-difluoro-benzyl ester hydrochloride

[0810] 1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene1-Bromo-2,4-difluoro-3-methyl-benzene (22 g, 0.106 M) andN-bromosuccinimide (22.7 g, 0.128 M) were dissolved intetrachloromethane (800 mL). Dibenzoylperoxide (0.52 g, 2 mM) was addedand the mixture was irradiated for 1 h. Succinimide was removed byfiltration of the cooled mixture and the filtrate was washed with water.The water phase was extracted with dichloromethane. Organic phases werepooled, dried with MgSO4 and and evaporated to yield a yellowish oil (32g). The residue was purified by column chromatography (silica gel;n-hexane) to yield 28.4 g (94%) of the title compound as a colorlessoil. MS (EI): 286.0 (M)⁺. (3-Bromo-2,6-difluoro-phenyl)-methanol

[0811] 1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene (45.2 g, 0.158 M)was dissolved in dioxane (800 mL), water (800 mL) and calcium carbonate(80 g, 0.80 M) were added and the mixture was refluxed for 16 h. Themixture was cooled, acidified with 2N HCl and extracted withdichloromethane. Organic phases were pooled, dried with Na2SO4 and andevaporated to yield a brownish oil (40.3 g). The residue was purified bycolumn chromatography (silica gel; n-hexane/ethyl acetate 9:1) to yield31.2 g (88%) of the title compound as a colorlesss solid. MS (EI): 224.0(M)⁺. cis-2,6-Dimethyl-piperazine-1,4-dicarboxylic acid 4-tert-butylester 1-(3-bromo-2,6-difluoro-benzyl)ester

[0812] The compound was prepared from(3-bromo-2,6-difluoro-phenyl)-methanol and4-chlorocarbonyl-cis-3,5-dimethyl-piperazine-1-carboxylic acidtert-butyl ester according to the procedures described in Example 121and 54 to give the product as a colorless oil (9.75 g); MS (ISP): 482.3(M+NH4)⁺. cis-2,6-Dimethyl-piperazine-1-carboxylic acid3-bromo-2,6-difluoro-benzyl ester hydrochloride

[0813] The compound was prepared fromcis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(3-bromo-2,6-difluoro-benzyl)ester according to the proceduresdescribed in Example 121 and 54 to give the product as a colorless solid(0.159 g); m.p.: 207-210° C.; MS (ISP): 365.1 (M+H)⁺.

Example 171

[0814] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,4-difluoro-2′-methoxy-biphenyl-3-ylmethyl ester

[0815] A mixture of 46.33 mg (0.1 mmol)cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester, 16.71 mg (0.11mmol) 2-methoxyphenylboronic acid, 3.65 mg (0.005 mmol) dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloromethaneadduct and 0.11 ml of a 2M Na₂CO₃ aq. solution in 1.2 ml dioxane washeated for 17 h to 85° C. The mixture was filtered and 0.15 ml 4N HCl indioxane was added and the mixture heated for 3 h to 65° C. After coolingto ambient temperature 0.2 ml triethylamine and water were added todissolve the mixture. The solution was subjected to reversed phasepreparative HPLC eluting with a water/acetonitrile gradient to yieldafter evaporation of the solvents 28.2 mg (66%) of the title compound.MS (ISP): 391 MH⁺.

[0816] In analogy to Example 171 the following Examples 172-176 can beprepared from given starting material that is either commerciallyavailable or described in the literature:

Example 172

[0817] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,4-difluoro-3′,4′-dimethoxy-biphenyl-3-ylmethyl ester hydrochloride

[0818] Following the general procedure of example 171 the title compoundwas synthesized from cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and3,4-dimethoxyphenyl boronic acid. MS (ISP): 421 MH⁺

Example 173

[0819] cis-2,6-Dimethyl-piperazine-1-carboxylic acid2,4-difluoro-3′-hydroxy-4′-methoxy-biphenyl-3-ylmethyl esterhydrochloride

[0820] Following the general procedure of example 171 the title compoundwas synthesized from cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol. MS(ISP): 407 MH⁺

Example 174

[0821] cis-2,6-Dimethyl-piperazine-1-carboxylic acid3′-amino-2,4-difluoro-biphenyl-3-ylmethyl ester hydrochloride

[0822] Following the general procedure of example 171 the title compoundwas synthesized from cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and3-aminophenyl boronic acid. MS (ISP): 376 MH⁺

Example 175

[0823] cis-2,6-Dimethyl-piperazine-1-carboxylic acid4′-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester hydrochloride

[0824] Following the general procedure of example 171 the title compoundwas synthesized from cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and4-acetyl-phenylboronic acid. MS (ISP): 403 MH⁺

Example 176

[0825] cis-2,6-Dimethyl-piperazine-1-carboxylic acid3′-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester hydrochloride

[0826] Following the general procedure of example 171 the title compoundwas synthesized from cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and3-acetyl-phenylboronic acid. MS (ISP): 403 MH⁺

Example 177

[0827] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-methyl-benzyl ester

[0828] (R)-2-Ethyl-piperazine dihydrochloride

[0829] (3R)-3-Ethyl-1-(phenylmethyl)-piperazine (30.7 g, 0.15 M) wasdissolved in ethanol (650 mL), palladium on carbon (10%; 11.5 g) wasadded and the mixture was hydrogenated (3 bar) at room temperature. Thecatalyst was removed by filtration and 5.5 N HCl in Ethanol (60 mL) wasadded to the filtrate. The product crystallized and was filtered offafter evaporation of 400 mL of the solvent and subsequent addition ofdiethylether (400 mL). White solid (25.9 g; 92%); MS (EI): 114.2 (M)⁺.

[0830] (R)-3-Ethyl-piperazine-1-carboxylic acid tert-butyl ester

[0831] (R)-2-Ethyl-piperazine dihydrochloride (25.9 g, 01.38 M) wasdissolved in dichloromethane (700 mL) and cooled to 0° C. Triethylamine(48.2 mL, 0.346 M) was added and subsequently di-tert-butyl-dicarbonate(30.2 g, 0.138 M) dissolved in dichloromethane (50 mL) was added within30 min with cooling (0-5° C.) and stirring. Stirring was continued foranother 3 h at room temperature. The mixture was washed with water, thewater phase was extracted twice with dichloromethane, organic phaseswere pooled, dried with Na2SO4 and evaporated to yield a colorless oil(31 g). The residue was purified by column chromatography (silica gel;dichoromethane/methanol 90:10) to yield 26.5 g (89%) of a colorless oil.MS (ISP): 215.5 (M+H)⁺.

[0832] (R)-4-Chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acidtert-butyl ester

[0833] Bis-(trichloromethyl)-carbonate (13.9 g, 47 mM) was dissolved indichloromethane (500 mL) and cooled to 0°0 C. A mixture of(R)-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester (26.5 g; 0.124M) and pyridine (10.9 mL, 0.136 M) in dichloromethane (150 mL) was addeddropwise with stirring (0-3° C.). Stirring was continued for another ½ hat room temperature. The mixture was washed with water and brine, thewater phases were extracted with dichloromethane, organic phases werepooled, dried with Na2SO4 and evaporated to yield a brown oil (34 g,99%) which crystallized upon standing; MS (EI): 276.2 (M)⁺.

[0834] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(3-bromo-2,6-difluoro-benzyl)ester

[0835] The compound was prepared from(3-bromo-2,6-difluoro-phenyl)-methanol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedures described in Example 121 and 54 togive the product as a colorless oil (9.22 g); MS (ISP): 480.3, 482.3(M+H)⁺.

[0836] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-methyl-benzyl)ester

[0837] A mixture of (R)-2-ethyl-piperazine-1,4-dicarboxylic acid4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl)ester (226 mg),tetrakis(triphenylphosphine)palladium (56 mg), trimethylboroxine (122mg) and potassium carbonate (200 mg) in dioxane (5 mL) was heated toreflux with stirring for 6 h. The cooled was mixture was partitionedbetween water and ethylacetate. The water phase was extracted once withethylacetate, organic phases were pooled and dried with Na2SO4 to yieldafter evaporation a dark oil (259 mg). This residue was purified bycolumn chromatography (silica gel; n-hexane/ethylacetate gradient) toyield 160 mg (82%) of a yellow oil. MS (ISP): 416.4 (M+H)⁺.

[0838] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-methyl-benzyl ester

[0839] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-methyl-benzyl)ester (160 mg) was dissolved in methanol(3 mL), 500 μL 4 N HCl in dioxane was added and the mixture was stirredfor 18 h at room temperature. The mixture was added to water (10 mL)made alkaline with 1 N NaOH and extracted with ethylacetate. Organicphases were pooled, dried with Na2SO4 and evaporated to give the productas a yellowish oil (120 mg); MS (ISP): 299.4 (M+H)⁺.

Example 178

[0840] (R)-2-Ethyl-piperazine-1-carboxylic acid 2,6-difluoro-benzylester

[0841] This compound was prepared from(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester and 2,6-difluorobenzylalcohol via(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-benzyl)ester according to the procedures described inExample 177 to give the product as a yellowish oil (69 mg); MS (ISP):285.2 (M+H)⁺.

Example 179

[0842] (R)-2-Ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester3,5-Difluoro-4-hydroxymethyl -phenol

[0843] 3,5-Difluorophenol (67.2 g, 0.48 M) was added to a solution ofpotassium hydroxide (35.1 g, 0.53 M) in water (145 mL). The mixture washeated to 60° C. and a mixture of formaldehyde (74 mL, 36% in water) andwater (145 mL) was added dropwise. The mixture was stirred for 20 h at40° C. After cooling to 0-5° C. concentrated HCl (60 mL, 36%) was added.The product precipitated, was filtered off and dried. Colorless solid(35.9 g, 41%); m.p.: 156-160° C. dec.; MS (ISN): 159.2 (M−H)⁻.

[0844] 4-Cyclopropylmethoxy-2,6-difluoro-benzylalcohol

[0845] Sodium hydride (82 mg, 55%, 1.87 mM) was added to a solution of3,5-difluoro-4-hydroxymethyl-phenol (300 mg, 1.87 mM) indimethylformamide (4 mL). After 1 h stirring at room temperaturecyclopropylmethylbromide (135 mg, 1.87 mM) was added and stirringcontinued for 24 h. The mixture was partitioned between water anddiethylether. Organic phases were pooled, washed with brine and driedwith MgSO4 to yield after evaporation a yellow oil (673 mg). Thisresidue was purified by column chromatography (silica gel;n-hexane/ethylacetate gradient) to yield 287 mg (71%) of the product asa yellowish oil. MS (EI): 214.1 (M)⁺.

[0846] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-cyclopropylmethoxy-2,6-difluoro-benzyl)ester

[0847] A mixture of 4-cyclopropylmethoxy-2,6-difluoro-benzylalcohol (270mg, 1.26 mM) and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylicacid tert-butyl ester (349 mg, 1.26 mM) in dimethylformamide (2 mL) wasadded slowly to a suspension of sodium hydride (83 mg, 55%, 1.89 mM) indimethylformamide (2 mL). The mixture was stirred at room temperaturefor 5 h and partitioned between water and diethylether. Organic phaseswere pooled, washed with brine and dried with MgSO4 to yield afterevaporation a yellow oil (585 mg). This residue was purified by columnchromatography (silica gel; n-hexane/ethylacetate gradient) to yield 406mg (71%) of the product as a yellowish oil. MS (ISP): 477.3 (M+H)⁺.

[0848] (R)-2-Ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester

[0849] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-cyclopropylmethoxy-2,6-difluoro-benzyl)ester (400 mg) was dissolvedin methanol (5 mL), 1100 μL 4 N HCl in dioxane was added and the mixturewas stirred for 18 h at room temperature. The mixture was made alkalinewith 2 N NaOH and eluted with ethylacetate over a column containing 10 gChemElut CE1010. The filtrate was collected, solvent was evaporated togive a yellowish oil (237 mg). This residue was purified by columnchromatography (silica gel; dichloromethane/methanol gradient) to yield186 mg (59%) of the product as a colorless oil. MS (ISP): 355.4 (M+H)⁺.

Example 180

[0850] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-propoxy-benzyl ester

[0851] 2,6-Difluoro-4-propoxy-benzylalcohol

[0852] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and propylbromide according to theprocedure described in Example 179 to give the product as a yellowishoil (168 mg, 44%); MS (EI): 202.1 (M)⁺.

[0853] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-propoxy-benzyl)ester

[0854] This compound was prepared from2,6-difluoro-4-propoxy-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (257 mg; 78%); MS (ISP): 465.4 (M+Na)⁺.

[0855] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-propoxy-benzyl ester

[0856] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-propoxy-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (133 mg;69%); MS (ISP): 343.4 (M+H)⁺.

Example 181

[0857] (R)-2-Ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester4-Allyloxy-2,6-difluoro-benzylalcohol

[0858] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and allylbromide according to theprocedure described in Example 179 to give the product as a yellowishoil (229 mg, 61%); MS (EI): 200.1 (M)⁺.

[0859] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-allyloxy-2,6-difluoro-benzyl)ester

[0860] This compound was prepared from4-allyloxy-2,6-difluoro-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (230 mg; 47%); MS (ISP): 441.4 (M+H)⁺.

[0861] (R)-2-Ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester

[0862] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-allyloxy-2,6-difluoro-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (101 mg;59%); MS (ISP): 341.4 (M+H)⁺.

Example 182

[0863] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester2,6-Difluoro-4-prop-2-ynyloxy-benzylalcohol

[0864] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and propargylbromide according tothe procedure described in Example 179 to give the product as ayellowish oil (229 mg, 62%); MS (EI): 197.1 (M)⁺.

[0865] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-prop-2-ynyloxy-benzyl)ester

[0866] This compound was prepared from2,6-difluoro-4-prop-2-ynyloxy-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (336 mg; 67%); MS (ISP): 456.5 (M+NH4)⁺.

[0867] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester

[0868] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-prop-2-ynyloxy-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (195 mg;76%); MS (ISP): 339.3(M+H)⁺.

Example 183

[0869] (R)-2-Ethyl-piperazine-1-carboxylic acid4-butoxy-2,6-difluoro-benzyl ester 4-Butoxy-2,6-difluoro-benzylalcohol

[0870] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and butylbromide according to theprocedure described in Example 179 to give the product as a yellowishoil (279 mg, 69%); MS (EI): 216.1 (M)⁺.

[0871] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-butoxy-2,6-difluoro-benzyl)ester

[0872] This compound was prepared from4-butoxy-2,6-difluoro-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (454 mg; 80%); MS (ISP): 479.4 (M+Na)⁺.

[0873] (R)-2-Ethyl-piperazine-1-carboxylic acid4-butoxy-2,6-difluoro-benzyl ester

[0874] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-butoxy-2,6-difluoro-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (240 mg;68%); MS (ISP): 357.4 (M+H)⁺.

Example 184

[0875] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl ester

[0876] 2,6-Difluoro-4-(2-methoxy-ethoxy)-benzylalcohol

[0877] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and methoxyethyl bromide accordingto the procedure described in Example 179 to give the product as acolorless oil (159 mg, 39%); MS (EI): 218.1 (M)⁺.

[0878] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl)ester

[0879] This compound was prepared from2,6-difluoro-(2-methoxy-ethoxy)-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (172 mg; 55%); MS (ISP): 481.4 (M+Na)⁺.

[0880] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl ester

[0881] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl)ester according to theprocedure described in Example 179 to give the product as a colorlessoil (75 mg; 56%); MS (ISP): 359.3(M+H)⁺.

Example 185

[0882] (R)-2-Ethyl-piperazine-1-carboxylic acid4-ethoxy-2,6-difluoro-benzyl ester

[0883] 4-Ethoxy-2,6-difluoro-benzylalcohol

[0884] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and ethylbromide according to theprocedure described in Example 179 to give the product as a yellowishoil (241 mg, 68%); MS (EI): 188.1 (M)⁺.

[0885] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-ethoxy-2,6-difluoro-benzyl)ester

[0886] This compound was prepared from4-ethoxy-2,6-difluoro-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (478 mg; 81%); MS (ISP): 429.6 (M+H)⁺.

[0887] (R)-2-Ethyl-piperazine-1-carboxylic acid4-ethoxy-2,6-difluoro-benzyl ester

[0888] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-ethoxy-2,6-difluoro-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (167 mg;46%); MS (ISP): 329.3 (M+H)⁺.

Example 186

[0889] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl ester

[0890] 2,6-Difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol

[0891] This compound was prepared from3,5-difluoro-4-hydroxymethyl-phenol and 4-chlormethyl-2-methylthiazolaccording to the procedure described in Example 179 to give the productas a colorless oil (369 mg, 73%); MS (ISP): 272.3 (M+H)⁺.

[0892] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl)ester

[0893] This compound was prepared from2,6-difluoro-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (447 mg; 66%); MS (ISP): 534.3 (M+Na)⁺.

[0894] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl ester

[0895] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl)ester accordingto the procedure described in Example 179 to give the product as acolorless oil (204 mg; 57%); MS (ISP): 412.4 (M+H)⁺.

Example 187

[0896] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-methoxy-benzyl ester hydrochloride2-Fluoro-5-iodo-benzylalcohol

[0897] 2-Fluoro-5-iodo-benzaldehyde (23.4 g, 0.093 M) was dissolved inmethanol (150 mL). Sodium borohydride (1.8 g, 0.047 M) was added inportions with cooling (5° C.) and stirring. The mixture was stirred for1 h at room temperature, poured into ice-water (600 mL) and extractedinto ethylacetate. Organic phases were pooled, washed with brine anddried with MgSO4. The solvent was evaporated to yield a yellowish oil(24.2 g). This residue was purified by column chromatography (silicagel; n-hexane/ethylacetate 4:1) to yield 23.9 g (quant.) of the productas a colorless oil. MS (EI): 252.0 (M)⁺.

[0898] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-iodo-benzyl)ester

[0899] A mixture of 2-fluoro-5-iodo-benzylalcohol (5.0 g, 19.8 mM) and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester (5.5 g, 19.8 mM) in dimethylformamide (70 mL) was added slowly toa suspension of sodium hydride (1.3 g, 55%, 1.89 mM) indimethylformamide (30 mL). The mixture was stirred at room temperaturefor 5 h and partitioned between water and diethylether. Organic phaseswere pooled, washed with brine and dried with Na2SO4 to yield afterevaporation a yellow oil (11.2 g). This residue was purified by columnchromatography (silica gel; n-hexane/ethylacetate 3:1) to yield 9.4 g(97%) of the product as a yellowish oil. MS (ISP): 510.3 (M+NH4)⁺.

[0900] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester

[0901] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-iodo-benzyl)ester (8.9 g, 18 mM) was dissolved intetrahydrofuran (150 mL), trisopropylborate (6.7 g, 36 mM) was added andthe mixture was cooled to -78° C. At this low temperature n-butyllithium(16.9 mL, 1.6N) was added drop by drop with stirring. The mixture wasstirred for 45 min at −78° C., for another 45 min at −50° C. and for 15min at 0° C. Acetic acid (9.5 mL, 50%) was added slowly with stirring(0-5° C.), followed by hydrogen peroxide (2.75 mL, 35%). Stirringcontinued with cooling for another 45 min and for 1 h at roomtemperature. The mixture was partitioned between water and diethylether,organic phases were pooled, washed with water, sodium thiosulfatesolution (5%), brine and dried with Na2SO4 to yield after evaporation alight yellow oil (8.5 g). This residue was purified by columnchromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 3.0 g(43%) of the product as a yellowish oil. MS (ISP): 400.5 (M+NH4)⁺.

[0902] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-methoxy-benzyl ester hydrochloride

[0903] A mixture of 6.27 mg (0.157 mmol) NaH (60% suspension in mineraloil) and 40 mg (0.105 mmol) (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid4-tert-butyl ester 1-(2-fluoro-5-hydroxy-benzyl)ester in 1 ml DMF wasstirred for 30 min at room temperature under argon. 16.4 mg (0.115 mmol)methyliodide was added and the mixture was stirred 30 min at roomtemperature. After addition of 60 ul HCl (37%) the mixture was purifiedwith preparative HPLC eluting with an acetonitrile/water gradient. Thefractions containing the desired intermediate were combined and 0.05 mlHCl (37%) was added before evaporation to dryness. The residue was takenup in 1 ml dioxane and 0.15 ml HCl (37%) and stirred for 30 min at 60°C. Evaporation of the mixture yielded 20 mg (57%) of the title compound.MS (ISP): 297 (M+H)⁺.

Example 188

[0904] (R)-2-Ethyl-piperazine-1-carboxylic acid 5-ethoxy-2-fluoro-benzylester hydrochloride

[0905] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and ethyl bromide. MS (ISP): 311(M+H)⁺.

Example 189

[0906] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-propoxy-benzyl ester hydrochloride

[0907] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and propyl bromide. MS (ISP): 325(M+H)⁺.

Example 190

[0908] (R)-2-Ethyl-piperazine-1-carboxylic acid 5-butoxy-2-fluoro-benzylester hydrochloride

[0909] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and butyl bromide. MS (ISP): 339(M+H)⁺.

Example 191

[0910] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-pentyloxy-benzyl ester hydrochloride

[0911] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and pentyl bromide. MS (ISP): 353(M+H)⁺.

Example 192

[0912] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-(3-methyl-butoxy)-benzyl ester hydrochloride

[0913] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 3-methyl-butyl bromide. MS (ISP):353 (M+H)⁺.

Example 193

[0914] (R)-2-Ethyl-piperazine-1-carboxylic acid5-benzyloxy-2-fluoro-benzyl ester

[0915] According to example 187 the title compound was synthesized from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and benzyl bromide. MS (ISP): 373(M+H)⁺.

Example 194

[0916] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-phenethyloxy-benzyl ester

[0917] According to example 187 the title compound was synthesized from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and phenethyl bromide. MS (ISP): 387(M+H)⁺.

Example 195

[0918] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-(2-methyl-benzyloxy)-benzyl ester hydrochloride

[0919] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 2-methylbenzyl bromide. MS (ISP):387 (M+H)⁺.

Example 196

[0920] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-(3-methyl-benzyloxy)-benzyl ester hydrochloride

[0921] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 3-methylbenzyl bromide. MS (ISP):387 (M+H)⁺.

Example 197

[0922] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-(2-pyrrol-1-yl-ethoxy)-benzyl ester

[0923] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 2-pyrrol-1-yl-ethyl bromide. MS(ISP): 375 (M+H)⁺.

Example 198

[0924] (R)-2-Ethyl-piperazine-1-carboxylic acid5-cyclopropylmethoxy-2-fluoro-benzyl ester hydrochloride

[0925] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and cyclopropylmethyl bromide. MS(ISP): 337 (M+H)⁺.

Example 199

[0926] (R)-2-Ethyl-piperazine-1-carboxylic acid5-cyclobutylmethoxy-2-fluoro-benzyl ester hydrochloride

[0927] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and cyclobutylmethyl bromide. MS(ISP): 351 (M+H)⁺.

Example 200

[0928] (R)-2-Ethyl-piperazine-1-carboxylic acid5-cyclohexylmethoxy-2-fluoro-benzyl ester hydrochloride

[0929] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and cyclohexylmethyl bromide. MS(ISP): 379 (M+H)⁺.

Example 201

[0930] (R)-2-Ethyl-piperazine-1-carboxylic acid5-(2-cyclohexyl-ethoxy)-2-fluoro-benzyl ester hydrochloride

[0931] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 2-cyclohexyl-ethyl bromide. MS(ISP): 393 (M+H)⁺.

Example 202

[0932] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-prop-2-ynyloxy-benzyl ester

[0933] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and prop-2-ynyl bromide. MS (ISP):337 (M+H)⁺.

Example 203

[0934] (R)-2-Ethyl-piperazine-1-carboxylic acid5-allyloxy-2-fluoro-benzyl ester

[0935] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and allyl bromide. MS (ISP): 323(M+H)⁺.

Example 204

[0936] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-(2-methoxy-ethoxy)-benzyl ester hydrochloride

[0937] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 2-methoxy-ethyl bromide. MS(ISP): 341 (M+H)⁺.

Example 205

[0938] (R)-2-Ethyl-piperazine-1-carboxylic acid5-(2-ethoxy-ethoxy)-2-fluoro-benzyl ester hydrochloride

[0939] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 2-ethoxy-ethyl bromide. MS (ISP):355 (M+H)⁺.

Example 206

[0940] (R)-2-Ethyl-piperazine-1-carboxylic acid2-fluoro-5-(3-phenoxy-propoxy)-benzyl ester hydrochloride

[0941] According to example 187 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and 3-phenoxy-propyl bromide. MS(ISP): 417 (M+H)⁺.

Example 207

[0942] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-methoxy-benzyl ester hydrochloride

[0943] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester

[0944] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(3-bromo-2,6-difluoro-benzyl)ester (3.9 g, 8 mM) was dissolved intetrahydrofuran (120 mL), trisopropylborate (3.1 g, 17 mM) was added andthe mixture was cooled to −78° C. At this low temperature n-butyllithium(7.8 mL, 1.6N) was added drop by drop with stirring. The mixture wasstirred for 45 min at −78° C., for another 45 min at −50° C. and for 15min at 0° C. Acetic acid (4.4 mL, 50%) was added slowly with stirring(0-5° C.), followed by hydrogen peroxide (1.3 mL, 35%). Stirringcontinued with cooling for another 45 min and for 1 h at roomtemperature. The mixture was partitioned between water and diethylether,organic phases were pooled, washed with water, sodium thiosulfatesolution (5%), brine and dried with Na2SO4 to yield after evaporation alight yellow oil (4.1 g). This residue was purified by columnchromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 0.93 g(28%) of the product as a colorless oil. MS (ISP): 418.2 (M+NH4)⁺.

[0945] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-methoxy-benzyl ester hydrochloride

[0946] A mixture of 5.03 mg (0.126 mmol) NaH (60% suspension in mineraloil) and 33.6 mg (0.084 mmol) (R)-2-Ethyl-piperazine-1,4-dicarboxylicacid 4-tert-butyl ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester in 1 mlDMF was stirred for 30 min at room temperature under argon. 13.1 mg(0.092 mmol) methyliodide was added and the mixture was stirred 30 minat room temperature. After addition of 0.06 ml HCl (37%) the mixture waspurified with preparative HPLC eluting with an acetonitrile/watergradient. The fractions containing the desired intermediate werecombined and evaporated to dryness. The residue was taken up in 1 mldioxane and 0.125 ml HCl (37%) and stirred for 30 min at 60° C.Evaporation of the mixture yielded 22 mg (75%) of the title compound. MS(ISP): 315 (M+H)⁺.

Example 208

[0947] (R)-2-Ethyl-piperazine-1-carboxylic acid3-ethoxy-2,6-difluoro-benzyl ester hydrochloride

[0948] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and ethyl bromide. MS (ISP): 329(M+H)⁺.

Example 209

[0949] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-propoxy-benzyl ester hydrochloride

[0950] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and propyl bromide. MS (ISP): 343(M+H)⁺.

Example 210

[0951] (R)-2-Ethyl-piperazine-1-carboxylic acid3-butoxy-2,6-difluoro-benzyl ester hydrochloride

[0952] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and butyl bromide. MS (ISP): 357(M+H)⁺.

Example 211

[0953] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-pentyloxy-benzyl ester hydrochloride

[0954] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and pentyl bromide. MS (ISP): 371(M+H)⁺.

Example 212

[0955] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-methyl-butoxy)-benzyl ester hydrochloride

[0956] According to example 207 the title compound was synthesized from(R)-2-Ethyl- piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-methyl-butyl bromide. MS(ISP): 371 (M+H)⁺.

Example 213

[0957] (R)-2-Ethyl-piperazine-1-carboxylic acid3-benzyloxy-2,6-difluoro-benzyl ester hydrochloride

[0958] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and benzyl bromide. MS (ISP): 391(M+H)⁺.

Example 214

[0959] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-phenyl-propoxy)-benzyl ester hydrochloride

[0960] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-phenyl-propyl bromide. MS(ISP): 419 (M+H)⁺.

Example 215

[0961] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(4-methyl-benzyloxy)-benzyl ester hydrochloride

[0962] According to example 207 the title compound was synthesized from(R)-2-Ethyl- piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 4-methyl-benzyl bromide. MS(ISP): 405 (M+H)⁺.

Example 216

[0963] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-methyl-benzyloxy)-benzyl ester hydrochloride

[0964] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-methyl-benzyl bromide. MS(ISP): 405 (M+H)⁺.

Example 217

[0965] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(2-methyl-benzyloxy)-benzyl ester hydrochloride

[0966] According to example 207 the title compound was synthesized from(R)-2-Ethyl- piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-methyl-benzyl bromide. MS(ISP): 205 (M+H)⁺.

Example 218

[0967] (R)-2-Ethyl-piperazine-1-carboxylic acid3-(3,3-dimethyl-butoxy)-2,6-difluoro-benzyl ester hydrochloride

[0968] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3,3-dimethylbutyl bromide. MS(ISP): 385 (M+H)⁺.

Example 219

[0969] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(2-pyrrol-1-yl-ethoxy)-benzyl ester hydrochloride

[0970] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-pyrrol-1-yl-ethyl bromide.MS (ISP): 394 (M+H)⁺.

Example 220

[0971] (R)-2-Ethyl-piperazine-1-carboxylic acid3-cyclopropylmethoxy-2,6-difluoro-benzyl ester hydrochloride

[0972] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-cyclopropylmethyl bromide.MS (ISP): 355 (M+H)⁺.

Example 221

[0973] (R)-2-Ethyl-piperazine-1-carboxylic acid3-cyclobutylmethoxy-2,6-difluoro-benzyl ester hydrochloride

[0974] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-cyclobutylmethyl bromide.MS (ISP): 369 (M+H)⁺.

Example 222

[0975] (R)-2-Ethyl-piperazine-1-carboxylic acid3-(2-cyclohexyl-ethoxy)-2,6-difluoro-benzyl ester hydrochloride

[0976] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-cyclohexyl-ethyl bromide.MS (ISP): 411 (M+H)⁺.

Example 223

[0977] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-prop-2-ynyloxy-benzyl ester hydrochloride

[0978] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and prop-2-ynyl bromide. MS(ISP): 339 (M+H)⁺.

Example 224

[0979] (R)-2-Ethyl-piperazine-1-carboxylic acid3-allyloxy-2,6-difluoro-benzyl ester hydrochloride

[0980] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and allyl bromide. MS (ISP): 341(M+H)⁺.

Example 225

[0981] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(2-methoxy-ethoxy)-benzyl ester hydrochloride

[0982] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-methoxy-ethyl bromide. MS(ISP): 359 (M+H)⁺.

Example 226

[0983] (R)-2-Ethyl-piperazine-1-carboxylic acid3-(2-ethoxy-ethoxy)-2,6-difluoro-benzyl ester hydrochloride

[0984] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-ethoxy-ethyl bromide. MS(ISP): 373 (M+H)⁺.

Example 227

[0985] (R)-2-Ethyl-piperazine-1-carboxylic acid2,6-difluoro-3-(3-phenoxy-propoxy)-benzyl ester hydrochloride

[0986] According to example 207 the title compound was synthesized from(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-phenoxy-propyl bromide. MS(ISP): 435 (M+H)⁺.

Example 228

[0987] (R)-2-Ethyl-piperazine-1-carboxylic1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]ester

[0988] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]ester

[0989] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-fluoro-5-hydroxy-benzyl)ester and toluene-4-sulfonic acid3-methoxy-propyl ester according to the procedure described in Example187 to give the product as a colorless oil (342 mg; 94%); MS (ISP):472.4 (M+NH4)⁺.

[0990] (R)-2-Ethyl-piperazine-1-carboxylic1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]ester

[0991] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]ester according to theprocedure described in Example 187 to give the product as a colorlessoil (154 mg; 64%); MS (ISP): 355.4 (M+H)⁺.

Example 229

[0992] (R)-2-Ethyl-piperazine-1-carboxylic acid1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]ester

[0993] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]ester

[0994] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2,6-difluoro-3-hydroxy-benzyl)ester and toluene-4-sulfonic acid3-methoxy-propyl ester according to the procedure described in Example207 to give the product as a colorless oil (117 mg; 97%); MS (ISP):490.4 (M+NH4)⁺.

[0995] (R)-2-Ethyl-piperazine-1-carboxylic acid1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]ester

[0996] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]ester according to theprocedure described in Example 207 to give the product as a colorlessoil (44 mg; 56%); MS (ISP): 373.4 (M+H)⁺.

Example 230

[0997] (R)-2-Ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester

[0998] 3-Chloro-5-fluoro-4-hydroxymethyl-phenol

[0999] This compound was prepared from 3-chloro-5-fluoro-phenol andformaldehyde according to the procedure described in Example 179 to givethe product as a colorless solid (26.4 g, 48%); m.p.: 125-127° C.; MS(EI): 176.1 (M)⁺.

[1000] 2-Chloro-4-cyclopropylmethoxy-6-fluoro-benzylalcohol

[1001] This compound was prepared from3-Chloro-5-fluoro-4-hydroxymethyl-phenol and cyclopropylmethylbromideaccording to the procedure described in Example 179 to give the productas a yellowish oil (305 mg, 77%); MS (EI): 230.1 (M)⁺.

[1002] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-4-cyclopropylmethoxy-6-fluoro-benzyl)ester

[1003] This compound was prepared from2-Chloro-4-cyclopropylmethoxy-6-fluoro-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (580 mg; 95%); MS (ISP): 488.4 (M+NH4)⁺.

[1004] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-4-cyclopropylmethoxy-6-fluoro-benzyl ester

[1005] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-4-cyclopropylmethoxy-6-fluoro-benzyl)ester according to theprocedure described in Example 179 to give the product as a colorlessoil (284 mg, 63%); MS (ISP): 371.3 (M+H)⁺.

Example 231

[1006] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-propoxy-benzyl ester

[1007] 2-Chloro-6-fluoro-4-propoxy-benzylalcohol

[1008] This compound was prepared from3-Chloro-5-fluoro-4-hydroxymethyl-phenol and propylbromide according tothe procedure described in Example 179 to give the product as ayellowish oil (259 mg, 69%); MS (EI): 218.1 (M)⁺.

[1009] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-propoxy-benzyl)ester

[1010] This compound was prepared from2-chloro-6-fluoro-4-propoxy-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (499 mg; 93%); MS (ISP): 476.3 (M+NH4)⁺.

[1011] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-propoxy-benzyl ester

[1012] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-propoxy-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (262 mg,68%); MS (ISP): 359.3 (M+H)⁺.

Example 232

[1013] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-ethoxy-benzyl ester

[1014] 2-Chloro-6-fluoro-4-ethoxy-benzylalcohol

[1015] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and ethylbromide according tothe procedure described in Example 179 to give the product as ayellowish oil (209 mg, 60%); MS (EI): 204.1 (M)⁺.

[1016] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-ethoxy-benzyl)ester

[1017] This compound was prepared from2-chloro-6-fluoro-4-ethoxy-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (418 mg; 94%); MS (ISP): 462.4 (M+NH4)⁺.

[1018] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-ethoxy-benzyl ester

[1019] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-ethoxy-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (205 mg,64%); MS (ISP): 345.4 (M+H)⁺.

Example 233

[1020] (R)-2-Ethyl-piperazine-1-carboxylic acid4-butoxy-2-chloro-6-fluoro-benzyl ester

[1021] 4-Butoxy-2-chloro-6-fluoro-benzylalcohol

[1022] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and butylbromide according tothe procedure described in Example 179 to give the product as ayellowish oil (277 mg, 70%); MS (EI): 232.1 (M)⁺.

[1023] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-butoxy-2-chloro-6-fluoro-benzyl)ester

[1024] This compound was prepared from4-butoxy-2-chloro-6-fluoro-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (505 mg; 90%); MS (ISP): 490.4 (M+NH4)⁺.

[1025] (R)-2-Ethyl-piperazine-1-carboxylic acid4-butoxy-2-chloro-6-fluoro-benzyl ester

[1026] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-butoxy-2-chloro-6-fluoro-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (286 mg;73%); MS (ISP): 373.4 (M+H)⁺.

Example 234

[1027] (R)-2-Ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester

[1028] 4-Allyloxy-2-chloro-6-fluoro-benzylalcohol

[1029] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and allylbromide according tothe procedure described in Example 179 to give the product as ayellowish oil (221 mg, 60%); MS (EI): 216.1 (M)⁺.

[1030] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-allyloxy-2-chloro-6-fluoro-benzyl)ester

[1031] This compound was prepared from4-allyloxy-2-chloro-6-fluoro-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (405 mg; 87%); MS (ISP): 474.4 (M+NH4)⁺.

[1032] (R)-2-Ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester

[1033] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(4-allyloxy-2-chloro-6-fluoro-benzyl)ester according to the proceduredescribed in Example 179 to give the product as a colorless oil (242 mg;78%); MS (ISP): 357.3 (M+H)⁺.

Example 235

[1034] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester

[1035] 2-Chloro-6-fluoro-4-prop-2-ynyloxy-benzylalcohol

[1036] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and propargylbromide accordingto the procedure described in Example 179 to give the product as ayellowish oil (212 mg, 58%); MS (EI): 214.1 (M)⁺.

[1037] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl)ester

[1038] This compound was prepared from2-chloro-6-fluoro-4-prop-2-ynyloxy-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (357 mg; 80%); MS (ISP): 472.3 (M+NH4)⁺.

[1039] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester

[1040] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl)ester according to theprocedure described in Example 179 to give the product as a colorlessoil (203 mg; 74%); MS (ISP): 355.3 (M+H)⁺.

Example 236

[1041] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzyl ester

[1042] 2-Chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzylalcohol

[1043] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and (2-bromoethyl)methyl etheraccording to the procedure described in Example 179 to give the productas a yellowish oil (209 mg, 52%); MS (EI): 234.1 (M)⁺.

[1044] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzyl)ester

[1045] This compound was prepared from2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (370 mg; 89%); MS (ISP): 492.3 (M+NH4)⁺.

[1046] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzyl ester

[1047] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzyl)ester according to theprocedure described in Example 179 to give the product as a colorlessoil (214 mg; 75%); MS (ISP): 375.4 (M+H)⁺.

Example 237

[1048] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzyl ester

[1049] 2-Chloro-6-fluoro-4-(3-methoxy-propoxy)-benzylalcohol

[1050] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and toluene-4-sulfonic acid3-methoxy-propyl ester according to the procedure described in Example179 to give the product as a yellowish oil (382 mg, 90%); MS (EI): 248.1(M)⁺.

[1051] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzyl)ester

[1052] This compound was prepared from2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (576 mg; 77%); MS (ISP): 506.4 (M+NH4)⁺.

[1053] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzyl ester

[1054] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzyl)ester according to theprocedure described in Example 179 to give the product as a colorlessoil (254 mg; 56%); MS (ISP): 389.3 (M+H)⁺.

Example 238

[1055] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl ester

[1056] 2-Chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol

[1057] This compound was prepared from3-chloro-5-fluoro-4-hydroxymethyl-phenol and 4-chloromethyl-2-thiazolaccording to the procedure described in Example 179 to give the productas a yellowish oil (421 mg, 86%); MS (EI): 287.0 (M)⁺.

[1058] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl)ester

[1059] This compound was prepared from2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol and(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butylester according to the procedure described in Example 179 to give theproduct as a colorless oil (582 mg; 75%); MS (ISP): 528.2 (M+H)⁺.

[1060] (R)-2-Ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl ester

[1061] This compound was prepared from(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester1-(2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl)esteraccording to the procedure described in Example 179 to give the productas a colorless oil (413 mg; 89%); MS (ISP): 428.5 (M+H)⁺.

EXAMPLE A

[1062] Tablets containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per tablet Compound of formula I10.0-300.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mgMagnesium stearate 1.0 mg

EXAMPLE B

[1063] Capsules containing the following ingredients can be manufacturedin a conventional manner: Ingredients Per capsule Compound of formula I100.0 mg Lactose 150.0 mg Maize starch  20.0 mg Talc  5.0 mg

EXAMPLE C

[1064] Injection solutions can have the following composition: Compoundof formula I 10.0 mg Sodium chloride q.s mg Water for injectionsolutions ad 2.0 ml

1. A compound of formula (I):

wherein R¹ and R² are independently selected from the group consistingof hydrogen, alkyl, cycloalkyl, aryl and aralkyl, or R¹ and R², togetherwith the carbon atom to which they are attached, form an unsubstituted3- to 8-membered carbocyclic ring or a 3 to 8 membered carbocyclic ringwhich is substituted with alkyl; R³ and R⁴ are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl andaralkyl; A¹ is oxygen or sulfur, wherein in case A¹ is oxygen and A² isunsubstituted phenyl one of R¹, R², R³ and R⁴ is not hydrogen; A² isunsubstituted aryl, unsubstituted heteroaryl or unsubstituted cycloalkylor aryl, heteroaryl or cycloalkyl each substituted with at least onesubstituent independently selected from the group consisting of halogen,alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy,cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl,cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy,heteroarylalkoxy, alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy andcycloalkylalkoxy, or wherein said alkyl, said cycloalkyl, said aryl,said aralkyl, said alkoxy, said aralkoxy, said aryloxy, saidalkoxycarbonyl, said cycloalkoxycarbonyl, said aryloxycarbonyl, saidaralkoxycarbonyl, said heteroaryloxycarbonyl, said cycloalkoxy, saidalkylsulfonyloxy, said arylsulfonyloxy, said heteroarylalkoxy, saidalkenyloxy, said tetrahydrofuranylalkoxy, said alkynyloxy and saidcycloalkylalkoxy are substituted with betweenone and three substituentsindependently selected from the group consisting of alkyl, alkoxy,halogen, nitro, oxo, trifluoromethyl, alkoxy substituted with betweenone and three halogen, thiophenyl, aryl, amino, alkylcarbonyl andaryloxy, or two substituents of aryl, heteroaryl or cycloalkyl form,together with the carbon atoms to which they are attached, anunsubstituted 5- to 7-membered carbocyclic ring or a substituted 5- to7-membered carbocyclic ring with at least one substituent independentlyselected from the group consisting of alkyl, alkoxy and halogen; n is 1or 2; and m is zero or 1; or a pharmaceutically acceptable salt, solvateor ester thereof; provided that 2-methyl-1-piperazinecarboxylic acid(4-nitrophenyl)methyl ester and 1-piperazinecarboxylic acid(4-(trifluoromethyl)phenyl)methyl ester are excluded.
 2. A compound offormula I according to claim 1, wherein A² is unsubstituted aryl,unsubstituted heteroaryl, unsubstituted cycloalkyl or aryl, heteroaryl,cycloalkyl each substituted with at least one substituent independentlyselected from the group consisting of halogen, alkyl, cycloalkyl, aryl,aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino,alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,heteroaryloxycarbonyl and carbamoyl, or wherein said alkyl, saidcycloalkyl, said aryl, said aralkyl, said alkoxy, said aralkoxy, saidaryloxy, said alkoxycarbonyl, said cycloalkoxycarbonyl, saidaryloxycarbonyl, said aralkoxycarbonyl and said heteroaryloxycarbonylare substituted with between one and three substituents independentlyselected from the group consisting of alkyl, alkoxy, halogen and nitro,or two substituents of aryl, heteroaryl or cycloalkyl form together withthe carbon atoms to which they are attached an unsubstituted 5- to7-membered carbocyclic ring or a 5- to 7-membered ring substituted withalkyl, alkoxy or halogen; and m is zero.
 3. A compound according toclaim 1, wherein R³ and R⁴ are independently selected from hydrogen oralkyl.
 4. A compound according to claim 3, wherein R³ and R⁴ arehydrogen.
 5. A compound according to claim 3, wherein R³ and R⁴ aremethyl.
 6. A compound according to claim 3, wherein one of R³ and R⁴ ismethyl or ethyl and the other of R³ and R⁴ is hydrogen.
 7. A compoundaccording to of claim 1, wherein A¹ is oxygen.
 8. A compound accordingto of claim 1, wherein A¹ is sulfur.
 9. A compound according to claim 1,wherein R¹ and R² are independently selected from the group consistingof hydrogen, alkyl and aryl.
 10. A compound according to claim 1,wherein A² is unsubstituted phenyl or phenyl substituted with betweenone and four substituents independently selected from the groupconsisting of halogen, alkoxy, carbamoyloxy, heteroarylalkoxy,alkenyloxy, alkynyloxy and cycloalkylalkoxy, or wherein said alkoxy,said heteroarylalkoxy or said alkenyloxy are substituted with betweenone and three substituents independently selected from alkyl or halogen.11. A compound according to claim 1, wherein A² is unsubstituted phenylor phenyl substituted with between one and three substituentsindependently selected from the group consisting of fluoro, chloro,difluoromethoxy, propoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy,2-propenyloxy, 5-pentyloxy, cyclopropylmethoxy, 2-propynyloxy andNH(R′)—C(O)—O—, wherein R′ is selected from the group consisting ofisopropyl, benzyl and tert.-butyl.
 12. A compound according to claim 1,wherein n is
 1. 13. A compound according to claim 12, wherein m is zero.14. A compound of formula I wherein the compound is selected from thegroup consisting of: S-4-[(2-propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate; S-4-[(benzylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate; S-4-[(tert-butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate; 2,6-difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate; (R)-4-difluoromethoxybenzyl2-ethylpiperazine-1-carboxylate; (R)-2,6-difluoro-4-propoxybenzyl2-methylpiperazine-1-carboxylate;cis-2,6-dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;2-fluoro-5-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate; (R)-2-fluoro-5-pentyloxybenzyl2-methylpiperazine-1-carboxylate;5-(cyclopropylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate;(R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester;(R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-4-propoxy-benzylester; (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester;(R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester;(R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester;(R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-propoxy-benzyl ester;(R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester; and(R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester.
 15. A compound offormula I wherein the compound is S-4-[(2-propylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate.
 16. A compound of formula I wherein thecompound is S-4-[(benzylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate.
 17. A compound of formula I wherein thecompound is S-4-[(tert-butylamino)carbonyl]oxybenzylpiperazine-1-thiocarboxylate.
 18. A compound of formula I wherein thecompound is 2,6-difluoro-4-difluoromethoxybenzylcis-2,6-dimethylpiperazine-1-carboxylate.
 19. A compound of formula Iwherein the compound is (R)-4-difluoromethoxybenzyl2-ethylpiperazine-1-carboxylate.
 20. A compound of formula I wherein thecompound is (R)-2,6-difluoro-4-propoxybenzyl2-methylpiperazine-1-carboxylate.
 21. A compound of formula I whereinthe compound is cis-2,6-dimethyl-piperazine-1-carboxylic acid4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester.
 22. Acompound of formula I wherein the compound is2-fluoro-5-(2-propenyl)oxybenzylcis-2,6-dimethylpiperazine-1-carboxylate.
 23. A compound of formula Iwherein the compound is (R)-2-fluoro-5-pentyloxybenzyl2-methylpiperazine-1-carboxylate.
 24. A compound of formula I whereinthe compound is 5-(cyclopropylmethyl)oxy-2-fluorobenzylcis-2,6-dimethylpiperazine-1-carboxylate.
 25. A compound of formula Iwherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2,6-difluoro-benzyl ester.
 26. A compound offormula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylicacid 2,6-difluoro-4-propoxy-benzyl ester.
 27. A compound of formula Iwherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2,6-difluoro-benzyl ester.
 28. A compound of formula Iwherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid2,6-difluoro-4-prop-2-ynyloxy-benzyl ester.
 29. A compound of formula Iwherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid4-cyclopropylmethoxy-2-chloro-6-fluoro-benzyl ester.
 30. A compound offormula I wherein the compound is (R)-2-ethyl-piperazine-1-carboxylicacid 2-chloro-6-fluoro-4-propoxy-benzyl ester.
 31. A compound of formulaI wherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid4-allyloxy-2-chloro-6-fluoro-benzyl ester.
 32. A compound of formula Iwherein the compound is (R)-2-ethyl-piperazine-1-carboxylic acid2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl ester.
 33. A process for thepreparation of a compound comprising deprotecting a compound of formula

wherein R¹ to R⁴, A¹, A², m and n are defined as in claim 1 and (P) is anitrogen protecting group.
 34. A method of treating a disease alleviatedby modulation of 5-HT2 receptors comprising administering atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt, solvate or ester thereof to a patientin need of such treatment.
 35. A pharmaceutical composition comprising atherapeutically effective amount of compound of formula I or apharmaceutically acceptable salt, solvate or ester thereof and atherapeutically inert carrier.
 36. The pharmaceutical composition ofclaim 35 further comprising a therapeutically effective amount of alipase inhibitor.
 37. The pharmaceutical composition of claim 36 whereinsaid lipase inhibitor is orlistat.
 38. A method of treating obesitycomprising administering a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt, solvate orester thereof to a patient in need of such treatment.
 39. The method ofclaim 38 further comprising the administration of a therapeuticallyeffective amount of a lipase inhibitor to the patient.
 40. The method oftreatment of claim 39 wherein said lipase inhibitor is orlistat.
 41. Amethod of treatment of diabetes mellitus, Type I diabetes, Type IIdiabetes, diabetes, diabetes secondary to pancreatic disease, diabetesrelated to steroid use, Type III diabetes, hyperglycaemia, diabeticcomplication and insulin resistance. diabetes comprising administrationof a therapeutically effective amount of the compound of formula I or apharmaceutically effective salt solvate or ester thereof to a patient inneed of such treatment.
 42. A method of treatment of type II diabetescomprises administering a therapeutically effective amount of a compoundof formula I or a pharmaceutically acceptable salt, solvate or esterthereof to a patient in need of such treatment.
 43. The method oftreatment of claim 42, further comprising administration of atherapeutically effective amount of a lipase inhibitor to the patient.44. The method of claim 43 wherein said lipase inhibitor is orlistat.